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Sample records for receptor antagonists block

  1. BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs.

    Science.gov (United States)

    Schmitz, Beate; Ullmer, Christoph; Segelcke, Daniel; Gwarek, Mirella; Zhu, Xin-Ran; Lübbert, Hermann

    2015-03-15

    Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.

  2. Bicuculline, a GABAA-receptor antagonist, blocked HPA axis activation induced by ghrelin under an acute stress.

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    Gastón, M S; Cid, M P; Salvatierra, N A

    2017-03-01

    Ghrelin is a peptide of 28 amino acids with a homology between species, which acts on the central nervous system to regulate different actions, including the control of growth hormone secretion and metabolic regulation. It has been suggested that central ghrelin is a mediator of behavior linked to stress responses and induces anxiety in rodents and birds. Previously, we observed that the anxiogenic-like behavior induced by ghrelin injected into the intermediate medial mesopallium (IMM) of the forebrain was blocked by bicuculline (a GABAA receptor competitive antagonist) but not by diazepam (a GABAA receptor allosteric agonist) in neonatal meat-type chicks (Cobb). Numerous studies have indicated that hypothalamic-pituitary-adrenal (HPA) axis activation mediates the response to stress in mammals and birds. However, it is still unclear whether this effect of ghrelin is associated with HPA activation. Therefore, we investigated whether anxiety behavior induced by intra-IMM ghrelin and mediated through GABAA receptors could be associated with HPA axis activation in the neonatal chick. In the present study, in an Open Field test, intraperitoneal bicuculline methiodide blocked anxiogenic-like behavior as well as the increase in plasma ACTH and corticosterone levels induced by ghrelin (30pmol) in neonatal chicks. Moreover, we showed for the first time that a competitive antagonist of GABAA receptor suppressed the HPA axis activation induced by an anxiogenic dose of ghrelin. These results show that the anxiogenic ghrelin action involves the activation of the HPA axis, with a complex functional interaction with the GABAA receptor.

  3. CP-465,022, a selective noncompetitive AMPA receptor antagonist, blocks AMPA receptors but is not neuroprotective in vivo.

    Science.gov (United States)

    Menniti, Frank S; Buchan, Alistair M; Chenard, Bertrand L; Critchett, Donald J; Ganong, Alan H; Guanowsky, Victor; Seymour, Patricia A; Welch, Willard M

    2003-01-01

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition has been hypothesized to provide neuroprotective efficacy after cerebral ischemia on the basis of the activity in experimental ischemia models of a variety of compounds with varying selectivity for AMPA over other glutamate receptor subtypes. CP-465,022 is a new, potent, and selective noncompetitive AMPA receptor antagonist. The present study investigated the ability of this compound to reduce neuronal loss after experimental cerebral ischemia to probe the neuroprotective potential of AMPA receptor inhibition. To demonstrate that CP-465,022 gains access to the brain, the effects of systemic administration of CP-465,022 were investigated on AMPA receptor-mediated electrophysiological responses in hippocampus and on chemically induced seizures in rats. The compound was then investigated for neuroprotective efficacy in rat global and focal ischemia models at doses demonstrated to be maximally effective in the electrophysiology and seizure models. CP-465,022 potently and efficaciously inhibited AMPA receptor-mediated hippocampal synaptic transmission and the induction of seizures. However, at comparable doses, CP-465,022 failed to prevent CA1 neuron loss after brief global ischemia or to reduce infarct volume after temporary middle cerebral artery occlusion. Given the high selectivity of CP-465,022 for AMPA over kainate and N-methyl-D-aspartate subtypes of glutamate receptors, the lack of neuroprotective efficacy of the compound calls into question the neuroprotective efficacy of AMPA receptor inhibition after ischemia.

  4. The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory.

    Science.gov (United States)

    Barsegyan, Areg; Atsak, Piray; Hornberger, Wilfried B; Jacobson, Peer B; van Gaalen, Marcel M; Roozendaal, Benno

    2015-07-01

    Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory.

  5. Interleukin-1 receptor antagonist is beneficial after subarachnoid haemorrhage in rat by blocking haem-driven inflammatory pathology

    Directory of Open Access Journals (Sweden)

    Andrew D. Greenhalgh

    2012-11-01

    Subarachnoid haemorrhage (SAH is a major contributor to the burden of stroke on society. Treatment options are limited and animal models of SAH do not always mimic key pathophysiological hallmarks of the disease, thus hindering development of new therapeutics. Inflammation is strongly associated with brain injury after SAH in animals and patients, and inhibition of the pro-inflammatory cytokine interleukin-1 (IL-1 represents a possible therapeutic target. Here we report that a rupture of the middle cerebral artery in the rat produces heterogeneous infarct patterns similar to those observed in human SAH. Administration of the IL-1 receptor antagonist (IL-1Ra reduced blood-brain barrier breakdown, and the extent of breakdown correlated with brain injury. After SAH, haem oxygenase-1 (HO-1 was strongly expressed around the bleed site and in the cortex and striatum, indicating the presence of free haem, a breakdown product of haemoglobin. HO-1 expression was also found in the same regions as microglial/macrophage expression of IL-1α. The direct effect of haem on IL-1α expression was confirmed in vitro using organotypic slice culture (OSC. Haem-induced cell death was dependent on IL-1 signalling, with IL-1Ra completely blocking cellular injury. Furthermore, stimulation of mouse primary mixed glial cells with haem induced the release of IL-1α, but not IL-1β. Thus, we suggest that haem, released from lysed red blood cells (RBCs in the subarachnoid space, acts as a danger-associated molecular pattern (DAMP driving IL-1-dependent inflammation. These data provide new insights into inflammation after SAH-induced brain injury and suggest IL-1Ra as a candidate therapeutic for the disease.

  6. Blocking S1P interaction with S1P{sub 1} receptor by a novel competitive S1P{sub 1}-selective antagonist inhibits angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Fujii, Yasuyuki, E-mail: y.fujii@po.rd.taisho.co.jp [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Ueda, Yasuji; Ohtake, Hidenori; Ono, Naoya; Takayama, Tetsuo; Nakazawa, Kiyoshi [Department of Molecular Function and Pharmacology Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Saitama, Saitama 331-9530 (Japan); Igarashi, Yasuyuki [Laboratory of Biomembrane and Biofunctional Chemistry, Hokkaido University, Sapporo, Hokkaido 060-0812 (Japan); Goitsuka, Ryo [Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022 (Japan)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer The effect of a newly developed S1P{sub 1}-selective antagonist on angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1} is a critical component of VEGF-related angiogenic responses. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vitro activity to inhibit angiogenesis. Black-Right-Pointing-Pointer S1P{sub 1}-selective antagonist showed in vivo activity to inhibit angiogenesis. Black-Right-Pointing-Pointer The efficacy of S1P{sub 1}-selective antagonist for anti-cancer therapies. -- Abstract: Sphingosine 1-phosphate receptor type 1 (S1P{sub 1}) was shown to be essential for vascular maturation during embryonic development and it has been demonstrated that substantial crosstalk exists between S1P{sub 1} and other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor. We developed a novel S1P{sub 1}-selective antagonist, TASP0277308, which is structurally unrelated to S1P as well as previously described S1P{sub 1} antagonists. TASP0277308 inhibited S1P- as well as VEGF-induced cellular responses, including migration and proliferation of human umbilical vein endothelial cells. Furthermore, TASP0277308 effectively blocked a VEGF-induced tube formation in vitro and significantly suppressed tumor cell-induced angiogenesis in vivo. These findings revealed that S1P{sub 1} is a critical component of VEGF-related angiogenic responses and also provide evidence for the efficacy of TASP0277308 for anti-cancer therapies.

  7. Extinction of conditioned opiate withdrawal in rats is blocked by intracerebroventricular infusion of an NMDA receptor antagonist.

    Science.gov (United States)

    Coleman, Brian R; Carlezon, William A; Myers, Karyn M

    2013-04-29

    Maladaptive conditioned responses (CRs) contribute to psychiatric disorders including anxiety disorders and addiction. Methods of reducing these CRs have been considered as possible therapeutic approaches. One such method is extinction, which involves exposure to CR-eliciting cues in the absence of the event they once predicted. In animal models, extinction reduces both fear and addiction-related CRs, and in humans, extinction-based cue exposure therapy (CET) reduces fear CRs. However, CET is less effective in drug addicts, for reasons that are not clear. Increased understanding of the neurobiology of extinction of drug-related CRs as compared to fear CRs may help illuminate this issue. Here, we examine the N-methyl-d-aspartate (NMDA) receptor-dependence of extinction of conditioned opiate withdrawal in rats. Using a place conditioning paradigm, we trained morphine-dependent rats to associate an environment with naloxone-precipitated withdrawal. We then extinguished that association by returning the rats repeatedly to the environment in the absence of acute withdrawal. In some rats we administered the NMDA receptor antagonist d,l-2-amino-5-phosphovaleric acid (AP5) intracerebroventricularly immediately prior to extinction training. In a subsequent test session, these rats avoided the formerly naloxone-paired environment, similar to rats that had not undergone extinction training. By contrast, rats that received vehicle prior to extinction training did not avoid the formerly naloxone-paired environment. This finding indicates that extinction of a drug-related CR (conditioned opiate withdrawal) is dependent on NMDA receptors, similar to extinction of conditioned fear. The locus of the critical NMDA receptors is unclear but may include basolateral amygdala and/or medial prefrontal cortex.

  8. Transient receptor potential ankyrin 1 antagonists block the noxious effects of toxic industrial isocyanates and tear gases.

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    Bessac, Bret F; Sivula, Michael; von Hehn, Christian A; Caceres, Ana I; Escalera, Jasmine; Jordt, Sven-Eric

    2009-04-01

    The release of methyl isocyanate in Bhopal, India, caused the worst industrial accident in history. Exposures to industrial isocyanates induce lacrimation, pain, airway irritation, and edema. Similar responses are elicited by chemicals used as tear gases. Despite frequent exposures, the biological targets of isocyanates and tear gases in vivo have not been identified, precluding the development of effective countermeasures. We use Ca(2+) imaging and electrophysiology to show that the noxious effects of isocyanates and those of all major tear gas agents are caused by activation of Ca(2+) influx and membrane currents in mustard oil-sensitive sensory neurons. These responses are mediated by transient receptor potential ankyrin 1 (TRPA1), an ion channel serving as a detector for reactive chemicals. In mice, genetic ablation or pharmacological inhibition of TRPA1 dramatically reduces isocyanate- and tear gas-induced nocifensive behavior after both ocular and cutaneous exposures. We conclude that isocyanates and tear gas agents target the same neuronal receptor, TRPA1. Treatment with TRPA1 antagonists may prevent and alleviate chemical irritation of the eyes, skin, and airways and reduce the adverse health effects of exposures to a wide range of toxic noxious chemicals.

  9. The orexin-1 receptor antagonist SB-334867 blocks the effects of antipsychotics on the activity of A9 and A10 dopamine neurons: implications for antipsychotic therapy.

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    Rasmussen, Kurt; Hsu, Mei-Ann; Yang, Yili

    2007-04-01

    Antipsychotic drugs alter the activity of dopamine neurons in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). As there is a dense projection of orexin neurons from the lateral hypothalamus to A10 dopaminergic neurons, and some antipsychotics have been shown to increase the expression of c-fos in orexin-containing cells in the hypothalamus, we hypothesized that stimulation of orexin receptors plays a role in the effects of antipsychotics on the activity of A9 and A10 dopamine cells. Single-unit recordings in anesthetized rats demonstrated the central effects of the selective orexin-1 receptor antagonist SB-334867 (2 mg/kg, intravenous), as it reversed the excitatory effects of orexin-A administration (6 microg, intracerebroventricular) on the activity of locus coeruleus (LC) cells. Recordings from midbrain dopamine neurons showed that acute administration of SB-334867 alone did not alter the number of spontaneously active A9 or A10 cells, but did reverse: (1) the increase in the number of spontaneously active A9 and/or A10 dopamine cells caused by the acute administration of haloperidol (1 mg/kg, subcutaneous) or olanzapine (10 mg/kg, s.c.) and (2) the decrease in the number of spontaneously active A9 and/or A10 dopamine cells caused by the chronic administration of haloperidol (1 mg/kg/day x 21 days, s.c.) or olanzapine (10 mg/kg/day x 21 days, s.c.). However, SB-334867 did not block a different electrophysiological effect of olanzapine, as it did not block the olanzapine-induced activation of LC cells. These results indicate that activation of orexin-1 receptors plays an important role on the effects of antipsychotic drugs on dopamine neuronal activity and may play an important role in the clinical effects of antipsychotic drugs.

  10. Systemic or intra-amygdala infusion of an endocannabinoid CB1 receptor antagonist AM251 blocked propofol-induced anterograde amnesia.

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    Ren, Y; Wang, J; Xu, P B; Xu, Y J; Miao, C H

    2015-01-01

    Propofol is well-known for its anterograde amnesic actions. However, a recent experiment showed that propofol can also produce retrograde memory enhancement effects via an interaction with the endocannabinoid CB1 system. Therefore, the authors hypothesized that the regulating effect of propofol on the endocannabinoid CB1 system might also decrease the anterograde amnesic effect of propofol under some conditions, which might be a risk factor for intraoperative awareness. Since, the basolateral amygdala (BLA) has been confirmed to mediate propofol-induced anterograde amnesia and the BLA contains a high concentration of CB1 receptors, the authors investigated whether and how the endocannabinoid system, particularly the CB1 receptor within BLA, influences propofol-induced anterograde amnesia. Male Sprague-Dawley rats trained with inhibitory avoidance (IA) were systematically pre-trained using a memory-impairing dose of propofol (25 mg/kg). Before propofol administration, rats received an intraperitoneal injection of a CB1 receptor antagonist AM251 (1 mg/kg or 2 mg/kg) or a bilateral intra-BLA injection of AM251 (0.6 ng or 6 ng per 0.5 μl). Twenty-four hours after IA training, the IA retention latency was tested. It was found that systemic or intra-BLA injection of a non-regulating dose of AM251 (2 mg/kg or 6 ng per 0.5 μl, respectively) blocked the memory-impairing effect of propofol. These results indicate that the anterograde amnesic effect of propofol is mediated, in part, by activation of the CB1 cannabinoid receptors in the BLA.

  11. The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

    NARCIS (Netherlands)

    Barsegyan, A.; Atsak, P.; Hornberger, W.B.; Jacobson, P.B.; Gaalen, M.M. van; Roozendaal, B.

    2015-01-01

    Stress-induced activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present s

  12. Intracerebroventricular injection of mu- and delta-opiate receptor antagonists block 60 Hz magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

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    Lai, H; Carino, M

    1998-01-01

    In previous research, we have found that acute exposure to a 60 Hz magnetic field decreased cholinergic activity in the frontal cortex and hippocampus of the rat as measured by sodium-dependent high-affinity choline uptake activity. We concluded that the effect was mediated by endogenous opioids inside the brain because it could be blocked by pretreatment of rats before magnetic field exposure with the opiate antagonist naltrexone, but not by the peripheral antagonist naloxone methiodide. In the present study, the involvement of opiate receptor subtypes was investigated. Rats were pretreated by intracerebroventricular injection of the mu-opiate receptor antagonist, beta-funaltrexamine, or the delta-opiate receptor antagonist, naltrindole, before exposure to a 60 Hz magnetic field (2 mT, 1 hour). It was found that the effects of magnetic field on high-affinity choline uptake in the frontal cortex and hippocampus were blocked by the drug treatments. These data indicate that both mu- and delta-opiate receptors in the brain are involved in the magnetic field-induced decreases in cholinergic activity in the frontal cortex and hippocampus of the rat.

  13. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  14. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  15. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala.

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    Fanselow, M S; Kim, J J

    1994-02-01

    Rats, with chronic cannula placed bilaterally in the amygdala, received infusions of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonovaleric acid (APV) before contextual Pavlovian fear conditioning. Administration of APV to the basolateral nucleus prevented acquisition of fear. Central nucleus infusions had no effect. It is concluded that an NMDA-mediated process near the basolateral region of the amygdala (e.g., lateral or basolateral nucleus) is essential for the learning of fear.

  16. Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle.

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    Cahusac, P M B; Mavulati, S C

    2009-10-20

    Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (dl-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly

  17. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  18. Beta-CCT, a selective BZ-omega1 receptor antagonist, blocks the anti-anxiety but not the amnesic action of chlordiazepoxide in mice.

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    Belzung, C; Le Guisquet, A M; Griebel, G

    2000-04-01

    The aim of this study was to test further the hypothesis that different benzodiazepine (BZ-omega) receptor subtypes may mediate anxiolytic and amnesic effects of BZ agonists, using the selective BZ-omega1 receptor antagonist beta-CCT (beta-carboline-3-carboxylate t-butyl-ester). Experiments were performed in Swiss mice using the elevated plus-maze anxiety test and two learning tasks - passive avoidance and the radial arm maze. In the elevated plus-maze test, beta-CCT (30 mg/kg, i.p.) completely abolished the increase in open-arm entries induced by the BZ chlordiazepoxide (5mg/kg, i.p.). Chlordiazepoxide decreased retention latency in the passive avoidance step-through procedure, and increased the number of errors in the radial arm maze. These effects were not modified by beta-CCT. Except for a slight, albeit significant, amnesic effect in the passive avoidance test, beta-CCT was devoid of intrinsic activity when administered alone. These results are in agreement with previous studies using selective BZ-omega1 agonists, and thus provide further evidence that BZ-omega1 receptors may be involved in the anxiolytic but not in the amnesic effects of BZ agonists.

  19. Bitopic Sphingosine 1-Phosphate Receptor 3 (S1P3) Antagonist Rescue from Complete Heart Block: Pharmacological and Genetic Evidence for Direct S1P3 Regulation of Mouse Cardiac Conduction

    Science.gov (United States)

    Sanna, M. Germana; Vincent, Kevin P.; Repetto, Emanuela; Nguyen, Nhan; Brown, Steven J.; Abgaryan, Lusine; Riley, Sean W.; Leaf, Nora B.; Cahalan, Stuart M.; Kiosses, William B.; Kohno, Yasushi; Brown, Joan Heller; McCulloch, Andrew D.

    2016-01-01

    The molecular pharmacology of the G protein–coupled receptors for sphingosine 1-phosphate (S1P) provides important insight into established and new therapeutic targets. A new, potent bitopic S1P3 antagonist, SPM-354, with in vivo activity, has been used, together with S1P3-knockin and S1P3-knockout mice to define the spatial and functional properties of S1P3 in regulating cardiac conduction. We show that S1P3 is a key direct regulator of cardiac rhythm both in vivo and in isolated perfused hearts. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in vivo and S1P in isolated hearts induced a spectrum of cardiac effects, ranging from sinus bradycardia to complete heart block, as measured by a surface electrocardiogram in anesthetized mice and in volume-conducted Langendorff preparations. The agonist effects on complete heart block are absent in S1P3-knockout mice and are reversed in wild-type mice with SPM-354, as characterized and described here. Homologous knockin of S1P3-mCherry is fully functional pharmacologically and is strongly expressed by immunohistochemistry confocal microscopy in Hyperpolarization Activated Cyclic Nucleotide Gated Potassium Channel 4 (HCN4)-positive atrioventricular node and His-Purkinje fibers, with relative less expression in the HCN4-positive sinoatrial node. In Langendorff studies, at constant pressure, SPM-354 restored sinus rhythm in S1P-induced complete heart block and fully reversed S1P-mediated bradycardia. S1P3 distribution and function in the mouse ventricular cardiac conduction system suggest a direct mechanism for heart block risk that should be further studied in humans. A richer understanding of receptor and ligand usage in the pacemaker cells of the cardiac system is likely to be useful in understanding ventricular conduction in health, disease, and pharmacology. PMID:26494861

  20. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  1. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  2. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels;

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties...... to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...

  3. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  4. Soman Induces Ictogenesis in the Amygdala and Interictal Activity in the Hippocampus That Are Blocked by a GluR5 Kainate Receptor Antagonist In Vitro

    Science.gov (United States)

    2009-01-01

    damage, with long-term neu- ological and behavioral consequences (McDonough et al., 986; Brown and Brix , 1998; Bajgar et al., 2004). Nerve gent–induced...raga MF, Aroniadou-Anderjaska V, Li H (2004) The physiological role of kainate receptors in the amygdala. Mol Neurobiol 30:127–141. rown MA, Brix KA

  5. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects....... In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET(A......) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  6. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  7. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  8. Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

    NARCIS (Netherlands)

    Petersson, K.J.; Vermeulen, A.M.J.; Friberg, L.E.

    2013-01-01

    Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess th

  9. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  10. HIGH AFFINITY ACYLATING ANTAGONISTS FOR MUSCARINIC RECEPTORS

    Science.gov (United States)

    Baumgold, Jesse; Karton, Yishai; Malka, Naftali; Jacobson, Kenneth A.

    2012-01-01

    Summary The muscarinic antagonists pirenzepine and telenzepine were derivitized as alkylamino derivatives at a site on the molecules corresponding to a region of bulk tolerance in receptor binding. The distal primary amino groups were coupled to the cross-linking reagent meta-phenylene diisothiocyanate, resulting in two isothiocyanate derivatives that were found to inhibit muscarinic receptors irreversibly and in a dose-dependent fashion. Preincubation of rat forebrain membranes with an isothiocyanate derivative followed by radioligand binding using [3H]N-methylscopolamine diminished the Bmax value, but did not affect the Kd value. The receptor binding site was not restored upon repeated washing, indicating that irreversible inhibition had occurred. IC50 values for the irreversible inhibition at rat forebrain muscarinic receptors were 0.15 nM and 0.19 nM, for derivatives of pirenzepine and telenzepine, respectively. The isothiocyanate derivative of pirenzepine was non-selective as an irreversible muscarinic inhibitor, and the corresponding derivative prepared from telenzepine was 5-fold selective for forebrain (mainly m1) vs. heart (m2) muscarinic receptors. PMID:1625525

  11. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  12. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  13. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  14. Calcium-sensing receptor antagonist (calcilytic) NPS 2143 specifically blocks the increased secretion of endogenous Aβ42 prompted by exogenous fibrillary or soluble Aβ25-35 in human cortical astrocytes and neurons-therapeutic relevance to Alzheimer's disease.

    Science.gov (United States)

    Armato, Ubaldo; Chiarini, Anna; Chakravarthy, Balu; Chioffi, Franco; Pacchiana, Raffaella; Colarusso, Enzo; Whitfield, James F; Dal Prà, Ilaria

    2013-10-01

    The "amyloid-β (Aβ) hypothesis" posits that accumulating Aβ peptides (Aβs) produced by neurons cause Alzheimer's disease (AD). However, the Aβs contribution by the more numerous astrocytes remains undetermined. Previously we showed that fibrillar (f)Aβ25-35, an Aβ42 proxy, evokes a surplus endogenous Aβ42 production/accumulation in cortical adult human astrocytes. Here, by using immunocytochemistry, immunoblotting, enzymatic assays, and highly sensitive sandwich ELISA kits, we investigated the effects of fAβ25-35 and soluble (s)Aβ25-35 on Aβ42 and Aβ40 accumulation/secretion by human cortical astrocytes and HCN-1A neurons and, since the calcium-sensing receptor (CaSR) binds Aβs, their modulation by NPS 2143, a CaSR allosteric antagonist (calcilytic). The fAβ25-35-exposed astrocytes and surviving neurons produced, accumulated, and secreted increased amounts of Aβ42, while Aβ40 also accrued but its secretion was unchanged. Accordingly, secreted Aβ42/Aβ40 ratio values rose for astrocytes and neurons. While slightly enhancing Aβ40 secretion by fAβ25-35-treated astrocytes, NPS 2143 specifically suppressed the fAβ25-35-elicited surges of endogenous Aβ42 secretion by astrocytes and neurons. Therefore, NPS 2143 addition always kept Aβ42/Aβ40 values to baseline or lower levels. Mechanistically, NPS 2143 decreased total CaSR protein complement, transiently raised proteasomal chymotrypsin activity, and blocked excess NO production without affecting the ongoing increases in BACE1/β-secretase and γ-secretase activity in fAβ25-35-treated astrocytes. Compared to fAβ25-35, sAβ25-35 also stimulated Aβ42 secretion by astrocytes and neurons and NPS 2143 specifically and wholly suppressed this effect. Therefore, since NPS 2143 thwarts any Aβ/CaSR-induced surplus secretion of endogenous Aβ42 and hence further vicious cycles of Aβ self-induction/secretion/spreading, calcilytics might effectively prevent/stop the progression to full-blown AD.

  15. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD.

    Science.gov (United States)

    Moulton, Bart C; Fryer, Allison D

    2011-05-01

    In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

  16. A pharmacophore model for dopamine D4 receptor antagonists

    Science.gov (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy

    2000-11-01

    A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D4 and D2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D2/D4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D2 receptor are shown to be present also in the D4 receptor. In addition, a novel receptor essential volume in the D4 receptor, not present in the D2 receptor, has been identified. This feature may be exploited for the design of D4 selective antagonists. However, it is concluded that the major determinant for D2/D4 selectivity is the nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.

  17. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    Energy Technology Data Exchange (ETDEWEB)

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  18. 7-Chloroarctinone-b as a new selective PPARγ antagonist potently blocks adipocyte differentiation

    Institute of Scientific and Technical Information of China (English)

    Yong-tao LI; Li LI; Jing CHEN; Tian-cen HU; Jin HUANG; Yue-wei GUO; Hua-liang JIANG; Xu SHEN

    2009-01-01

    Aim: Peroxisome proliferator-activated receptor gamma (PPARy) is a therapeutic target for obesity, cancer and diabetes mellitus. In order to develop potent lead compounds for obesity treatment, we screened a natural product library for novel PPARy antagonists with inhibitory effects on adipocyte differentiation. Methods: Surface plasmon resonance (SPR) technology and cell-based transactivation assay were used to screen for PPARy antago-nists. To investigate the antagonistic mechanism of the active compound, we measured its effect on PPARy/RXRα heterodimerization and PPARy co-activator recruitment using yeast two-hybrid assay, Gal4/UAS cell-based assay and SPR based assay. The 3T3-L1 cell differentiation assay was used to evaluate the effect of the active compound on adipocyte differentiation. Results: A new thiophene-acetylene type of natural product, 7-chloroarctinone-b (CAB), isolated from the roots of Rhaponticum uniflo-rum, was discovered as a novel PPARγ antagonist capable of inhibiting rosiglitazone-induced PPARγ transcriptional activity. SPR analy-sis suggested that CAB bound tightly to PPARγ and considerably antagonized the potent PPARy agonist rosigtitazone-stimulated PPARγ-LBD/RXRα-LBD binding. Gal4/UAS and yeast two-hybrid assays were used to evaluate the antagonistic activity of CAB on rosiglitazone-induced recruitment of the coactivator for PPARy. CAB could efficiently antagonize both hormone and rosiglitazone-induced adipocyte differentiation in cell culture. Conclusion: CAB shows antagonistic activity to PPARγ and can block the adipocyte differentiation, indicating it may be of potential use as a lead therapeutic compound for obesity.

  19. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  20. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-09-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  1. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    OpenAIRE

    Mohammad eKhanfar; Anna eAffini; Kiril eLutsenko; Katarina eNikolic; Stefania eButini; Holger eStark

    2016-01-01

    With the very recent market approval of pitolisant (Wakix®), the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex...

  2. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  3. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  4. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian;

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  5. Serotonin receptor antagonists discriminate between PKA- and PKC-mediated plasticity in aplysia sensory neurons.

    Science.gov (United States)

    Dumitriu, Bogdan; Cohen, Jonathan E; Wan, Qin; Negroiu, Andreea M; Abrams, Thomas W

    2006-04-01

    Highly selective serotonin (5-hydroxytryptamine, 5-HT) receptor antagonists developed for mammals are ineffective in Aplysia due to the evolutionary divergence of neurotransmitter receptors and because the higher ionic strength of physiological saline for marine invertebrates reduces antagonist affinity. It has therefore been difficult to identify antagonists that specifically block individual signaling cascades initiated by 5-HT. We studied two broad-spectrum 5-HT receptor antagonists that have been characterized biochemically in Aplysia CNS: methiothepin and spiperone. Methiothepin is highly effective in inhibiting adenylyl cyclase (AC)-coupled 5-HT receptors in Aplysia. Spiperone, which blocks phospholipase C (PLC)-coupled 5-HT receptors in mammals, does not block AC-coupled 5-HT receptors in Aplysia. In electrophysiological studies, we explored whether methiothepin and spiperone can be used in parallel to distinguish between the AC-cAMP and PLC-protein kinase C (PKC) modulatory cascades that are initiated by 5-HT. 5-HT-induced broadening of the sensory neuron action potential in the presence of tetraethylammonium/nifedipine, which is mediated by modulation of the S-K+ currents, was used an assay for the AC-cAMP cascade. Spike broadening initiated by 5 microM 5-HT was unaffected by 100 microM spiperone, whereas it was effectively blocked by 100 microM methiothepin. Facilitation of highly depressed sensory neuron-to-motor neuron synapses by 5-HT was used as an assay for the PLC-PKC cascade. Spiperone completely blocked facilitation of highly depressed synapses by 5 microM 5-HT. In contrast, methiothepin produced a modest, nonsignificant, reduction in the facilitation of depressed synapses. Interestingly, these experiments revealed that the PLC-PKC cascade undergoes desensitization during exposure to 5-HT.

  6. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  7. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  8. Approaches to the rational design of selective melanocortin receptor antagonists

    Science.gov (United States)

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  9. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

    Science.gov (United States)

    Sica, Domenic A

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  10. Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

    Science.gov (United States)

    Skovbakke, Sarah Line; Holdfeldt, André; Nielsen, Christina; Hansen, Anna Mette; Perez-Gassol, Iris; Dahlgren, Claes; Forsman, Huamei; Franzyk, Henrik

    2017-08-24

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.

  11. Blocking the peroxisome proliferator-activated receptor (PPAR): an overview.

    Science.gov (United States)

    Ammazzalorso, Alessandra; De Filippis, Barbara; Giampietro, Letizia; Amoroso, Rosa

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Microglial inhibition of neuroprotection by antagonists of the EP1 prostaglandin E2 receptor

    Directory of Open Access Journals (Sweden)

    Rojas Monica A

    2009-02-01

    Full Text Available Abstract Background The EP1 receptor for the prostanoid PGE2 is a G-protein coupled receptor that has been shown to contribute to excitotoxic neuronal death. In this study we examined the influence of non-neuronal cells on neuroprotective properties of EP1 receptor antagonists (Ono 8711 and SC 51089. Methods Primary neuronal cultures systems with or without non-neuronal cells were used to examine how the neuroprotective properties of EP1 antagonists were influenced by non-neuronal cells. The influence of astrocytes or microglia were individually tested in excitotoxicity assays using a co-culture system with these cells grown on permeable transwell inserts above the neuronal-enriched cultures. The influence of microglia on PGE2 synthesis and EP1 receptor expression was examined. Results EP1 antagonists were neuroprotective in neuronal-enriched cultures (> 90% neurons but not in mixed cultures (30% neurons plus other non-neuronal cells. Co-cultures of microglia on permeable transwell inserts above neuronal-enriched cultures blocked neuroprotection by EP1 antagonists. Incubation of microglia with neuronal-enriched cultures for 48 hours prior to NMDA challenge was sufficient to block neuroprotection by EP1 antagonists. The loss of neuroprotection by EP1 antagonists was accompanied by a decrease of neuronal EP1 expression in the nucleus in cultures with microglia present. Conclusion These findings demonstrate microglial modulation of neuronal excitotoxicity through interaction with the EP1 receptor and may have important implications in vivo where microglia are associated with neuronal injury.

  13. Bradykinin as a pain mediator: receptors are localized to sensory neurons, and antagonists have analgesic actions

    Energy Technology Data Exchange (ETDEWEB)

    Steranka, L.R.; Manning, D.C.; DeHaas, C.J.; Ferkany, J.W.; Borosky, S.A.; Connor, J.R.; Vavrek, R.J.; Stewart, J.M.; Snyder, S.H.

    1988-05-01

    Autoradiographic studies localize (/sup 3/H)bradykinin receptor binding sites to the substantia gelatinosa, dorsal root, and a subset of small cells in both the dorsal root and trigeminal ganglia of the guinea pig. (/sup 3/H)Bradykinin labeling is also observed over myocardinal/coronary visceral afferent fibers. The localization of (/sup 3/H)bradykinin receptors to nociceptive pathways supports a role for bradykinin in pain mediation. Several bradkykinin antagonists block bradykinin-induced acute vascular pain in the rat. The bradykinin antagonists also relieve bradykinin- and urate-induced hyperalgesia in the rat paw. These results indicate that bradykinin is a physiologic mediator of pain and that bradykinin antagonists have analgesic activity in both acute and chronic pain models.

  14. Blonanserin, an antipsychotic and dopamine D₂/D₃receptor antagonist, and ameliorated alcohol dependence.

    Science.gov (United States)

    Takaki, Manabu; Ujike, Hiroshi

    2013-01-01

    Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak α1 receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D₃ receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D₃ receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence.

  15. Endothelin receptor antagonists influence cardiovascular morphology in uremic rats.

    Science.gov (United States)

    Nabokov, A V; Amann, K; Wessels, S; Münter, K; Wagner, J; Ritz, E

    1999-02-01

    In is generally held that renal failure results in blood pressure (BP)-independent structural changes of the myocardium and the vasculature. The contribution, if any, of endothelin (ET) to these changes has been unknown. We morphometrically studied random samples of the left ventricle myocardium and small intramyocardial arteries in subtotally (5/6) nephrectomized (SNx) male Sprague-Dawley rats treated with either the selective ETA receptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB receptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-operated rats, untreated SNx, or SNx rats treated with the angiotensin-converting enzyme inhibitor trandolapril (0.1 mg/kg/day). Eight weeks later, systolic BP was lower in trandolapril-treated SNx compared with untreated SNx animals. No decrease in BP was seen following either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx rats as compared with sham-operated controls. Such interstitial expansion was prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteries. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups when compared with untreated SNx. In contrast, only trandolapril, but not the ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. The ETA-selective and ETA/ETB-nonselective receptor antagonists appear to prevent development of myocardial fibrosis and structural changes of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.

  16. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  17. Drug discovery and chemokine receptor antagonists: eppur si muove!

    Science.gov (United States)

    Terricabras, Emma; Benjamim, Claudia; Godessart, Nuria

    2004-11-01

    The blockade of leukocyte migration has been demonstrated to be a valid option for the treatment of several autoimmune diseases. Chemokines play an active role in regulating cell infiltration into inflammatory sites and disrupting chemokine-receptor interactions has emerged as an alternative therapeutic approach. Pharmaceutical companies have developed an intense activity in the drug discovery of chemokine receptor antagonists in the last 10 years. Potent and selective compounds have been obtained and some of them are currently being evaluated in the clinic. The success of these trials will demonstrate whether the blockade of a single receptor is of therapeutic benefit. Alternative approaches, such as pan-receptor antagonists or inhibitors of the signalling pathways evoked by chemokines, are also being explored. In the meantime, new relationships between chemokines and receptors will be revealed, increasing our knowledge of such a fascinating field.

  18. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    swelling and pain determined, along with initial experiments on the chemokine receptor antagonist (CRA) AMD3100. Methods were established for measuring a...Presentations………………………….22 7. Inventions , Patents and Licenses……………………..………….22 8. Reportable Outcomes……………………………………………….22 9. Other Achievements...Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain; Chemokine and cytokine measurements 3. OVERALL PROJECT

  19. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  20. The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide.

    Science.gov (United States)

    Fox, M A; Levine, E S; Riley, A L

    2001-01-01

    To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

  1. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  2. Neurokinin-1 receptor antagonists for chemotherapy-induced nausea and vomiting.

    Science.gov (United States)

    Aziz, Fahad

    2012-07-01

    Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. The discovery of several NK1 receptor antagonists is a big revolution to dealt this problem. NK1 receptor antagonists prevent both acute and delayed chemotherapy-induced nausea and vomiting (CINV). These agents act centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, these agents help improve patients' daily living and their ability to complete multiple cycles of chemotherapy. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

  3. Therapeutic Opportunities for Caffeine and A2A Receptor Antagonists in Retinal Diseases.

    Science.gov (United States)

    Boia, Raquel; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-01-01

    Caffeine, the major component of coffee, is the most consumed psychostimulant in the world. Caffeine is an adenosine analog and acts as a nonselective adenosine receptor antagonist. The majority of the effects of caffeine are mainly mediated by the blockade of adenosine receptors, and the proved neuroprotective effects of caffeine in brain disorders have been mimicked by the blockade of adenosine A2A receptor (A2AR). A growing body of evidence demonstrates that microglia-mediated neuroinflammation plays a key role in the pathophysiology of brain and retinal diseases. Moreover, the control of microglia reactivity by blocking A2AR has been proposed to be the mechanism underlying the observed protective effects of caffeine. Hence, it is conceivable that caffeine and A2AR antagonists offer therapeutic value for the treatment of retinal diseases, mainly those involving microglia-mediated neuroinflammation.

  4. Characterization of mechanisms involved in presynaptic inhibition of sympathetic pressor effects induced by some 5-HT1 receptor antagonists.

    Science.gov (United States)

    Fernández, M M; Calama, E; Morán, A; Martín, M L; San Román, L

    2000-01-01

    1. In a previous study, we showed that the presynaptic inhibitory action of 5-hydroxytryptamine receptor agonists on sympathetic pressor effects obtained in the pithed rats were mainly mediated by activation of 5-HT1A and 5-HT1D receptor subtypes. At the time, we observed that some 5-HT1 receptors antagonists - WAY 100,635 and NAN-190 (both 5-HT1A receptor antagonists), methiothepin (a 5-HT1,2,5,6,7 receptor antagonist) and spiperone (a 5-HT1,2 receptor antagonist) - reduced per se the pressor effects obtained by electrical stimulation. The aim of the present work was to investigate the mechanism participating in this inhibitory effect. 2. The inhibition induced by WAY 100,635 (1000 microg kg-1, i.v.) was blocked after i.v. treatment with idazoxan, an alpha2-adrenoceptor antagonist (300 and 1000 microg kg-1) and was not modified after i.v. treatment with propranolol, a beta-adrenoceptor antagonist (1000 microg kg-1) and sulpiride, a D2 receptor antagonist (1000 microg kg-1). The inhibition induced by spiperone (500 microg kg-1 i.v.) was significantly blocked by sulpiride (1000 microg kg-1) and was not modified by idazoxan or propranolol. 3. Sulpiride (1000 microg kg-1) partially blocked the inhibition induced by methiothepin (50 microg kg-1 i.v.). Only pretreatment with idazoxan (300 microg kg-1) modified the inhibition induced by NAN-190 (100 microg kg-1 i.v.), such inhibition increasing after intravenous administration of idazoxan. 4. All the antagonists used in our experiments failed to inhibit the pressor responses elicited by i.v. noradrenaline administration. 5. The above results suggest that the inhibitory effects of these 5-HT1 receptor antagonists are presynaptic in nature, but not related to the blockade of 5-HT1 receptors subtypes. The simultaneous activation or inhibition of other receptor systems could explain the inhibition produced by each 5-HT1 receptor antagonist studied.

  5. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...

  6. Tetrazolyl isoxazole amino acids as ionotropic glutamate receptor antagonists: synthesis, modelling and molecular pharmacology.

    Science.gov (United States)

    Frølund, Bente; Greenwood, Jeremy R; Holm, Mai M; Egebjerg, Jan; Madsen, Ulf; Nielsen, Birgitte; Bräuner-Osborne, Hans; Stensbøl, Tine B; Krogsgaard-Larsen, Povl

    2005-09-15

    Two 3-(5-tetrazolylmethoxy) analogues, 1a and 1b, of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), a selective AMPA receptor agonist, and (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl)propionic acid (ATPA), a GluR5-preferring agonist, were synthesized. Compounds 1a and 1b were pharmacologically characterized in receptor binding assays, and electrophysiologically on homomeric AMPA receptors (GluR1-4), homomeric (GluR5 and GluR6) and heteromeric (GluR6/KA2) kainic acid receptors, using two-electrode voltage-clamped Xenopus laevis oocytes expressing these receptors. Both analogues proved to be antagonists at all AMPA receptor subtypes, showing potencies (Kb=38-161 microM) similar to that of the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4-isoxazolyl]propionic acid (AMOA) (Kb=43-76 microM). Furthermore, the AMOA analogue, 1a, blocked two kainic acid receptor subtypes (GluR5 and GluR6/KA2), showing sevenfold preference for GluR6/KA2 (Kb=19 microM). Unlike the iGluR antagonist (S)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid [(S)-ATPO], the corresponding tetrazolyl analogue, 1b, lacks kainic acid receptor effects. On the basis of docking to a crystal structure of the isolated extracellular ligand-binding core of the AMPA receptor subunit GluR2 and a homology model of the kainic acid receptor subunit GluR5, we were able to rationalize the observed structure-activity relationships.

  7. Kappa opioid receptor antagonist and N-methyl-D- aspartate receptor antagonist affect dynorphin- induced spinal cord electrophysiologic impairment

    Institute of Scientific and Technical Information of China (English)

    Yu Chen; Liangbi Xiang; Jun Liu; Dapeng Zhou; Hailong Yu; Qi Wang; Wenfeng Han; Weijian Ren

    2012-01-01

    The latencies of motor- and somatosensory-evoked potentials were prolonged to different degrees, and wave amplitude was obviously decreased, after injection of dynorphin into the rat subarachnoid cavity.The wave amplitude and latencies of motor- and somatosensory-evoked potentials were significantly recovered at 7 and 14 days after combined injection of dynorphin and either the kappa opioid receptor antagonist nor-binaltorphimine or the N-methyl-D-aspartate receptor antagonist MK-801.The wave amplitude and latency were similar in rats after combined injection of dynorphin and nor-binaltorphimine or MK-801.These results suggest that intrathecal injection of dynorphin causes damage to spinal cord function.Prevention of N-methyl-D-aspartate receptor or kappa receptor activation lessened the injury to spinal cord function induced by dynorphin.

  8. Aldosterone receptor antagonists: current perspectives and therapies

    OpenAIRE

    Guichard JL; Clark III D; Calhoun DA; Ahmed MI

    2013-01-01

    Jason L Guichard, Donald Clark III, David A Calhoun, Mustafa I Ahmed University of Alabama at Birmingham, Department of Medicine, Division of Cardiovascular Disease, Vascular Biology and Hypertension Program, Birmingham, AL, USA Abstract: Aldosterone is a downstream effector of angiotensin II in the renin–angiotensin–aldosterone system and binds to the mineralocorticoid receptor. The classical view of aldosterone primarily acting at the level of the kidneys to regulate pl...

  9. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  10. The cholecystokinin-B receptor antagonist CI-988 failed to affect CCK-4 induced symptoms in panic disorder patients

    NARCIS (Netherlands)

    vanMegen, HJGM; Westenberg, HGM; denBoer, JA; Slaap, B; vanEsRadhakishun, F; Pande, AC

    1997-01-01

    The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder. The study employed a double-blind, two-period incomplete block design. Patients (n = 14) received two differe

  11. μ Opioid receptor: novel antagonists and structural modeling

    Science.gov (United States)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  12. Antagonistic action of pitrazepin on human and rat GABAA receptors

    Science.gov (United States)

    Demuro, Angelo; Martinez-Torres, Ataulfo; Francesconi, Walter; Miledi, Ricardo

    1999-01-01

    Pitrazepin, 3-(piperazinyl-1)-9H-dibenz(c,f) triazolo(4,5-a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABAA antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding α1β2 or α1β2γ2S human GABAA receptor subunits.The three types of GABAA receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration-dependent manner. GABA dose-current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin.Schild analyses gave pA2 values of 6.42±0.62, n=4, 6.41±1.2, n=5 and 6.21±1.24, n=6, in oocytes expressing rat cerebral cortex, α1β2 or α1β2γ2S human GABAA receptors respectively (values are given as means±s.e.mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABAA receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied.Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15-1788 (flumazenil) on the inhibition of α1β2γ2S receptors by pitrazepin. Co-application of Ro 15-1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA-currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor-chloride channel by interacting with the benzodiazepine receptor site. PMID:10369456

  13. Aryl biphenyl-3-ylmethylpiperazines as 5-HT7 receptor antagonists.

    Science.gov (United States)

    Kim, Jeeyeon; Kim, Youngjae; Tae, Jinsung; Yeom, Miyoung; Moon, Bongjin; Huang, Xi-Ping; Roth, Bryan L; Lee, Kangho; Rhim, Hyewhon; Choo, Il Han; Chong, Youhoon; Keum, Gyochang; Nam, Ghilsoo; Choo, Hyunah

    2013-11-01

    The 5-HT7 receptor (5-HT7 R) is a promising therapeutic target for the treatment of depression and neuropathic pain. The 5-HT7 R antagonist SB-269970 exhibited antidepressant-like activity, whereas systemic administration of the 5-HT7 R agonist AS-19 significantly inhibited mechanical hypersensitivity and thermal hyperalgesia. In our efforts to discover selective 5-HT7 R antagonists or agonists, aryl biphenyl-3-ylmethylpiperazines were designed, synthesized, and biologically evaluated against the 5-HT7 R. Among the synthesized compounds, 1-([2'-methoxy-(1,1'-biphenyl)-3-yl]methyl)-4-(2-methoxyphenyl)piperazine (28) was the best binder to the 5-HT7 R (pKi =7.83), and its antagonistic property was confirmed by functional assays. The selectivity profile of compound 28 was also recorded for the 5-HT7 R over other serotonin receptor subtypes, such as 5-HT1 R, 5-HT2 R, 5-HT3 R, and 5-HT6 R. In a molecular modeling study, the 2-methoxyphenyl moiety attached to the piperazine ring of compound 28 was proposed to be essential for the antagonistic function.

  14. A cannabinoid CB(1) receptor antagonist ameliorates impairment of recognition memory on withdrawal from MDMA (Ecstasy).

    Science.gov (United States)

    Nawata, Yoko; Hiranita, Takato; Yamamoto, Tsuneyuki

    2010-01-01

    (+/-)-3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') abusers have persistent neuropsychiatric deficits including memory impairments after the cessation of abuse. On the other hand, cannabinoid CB(1) receptors have been implicated in learning/memory, and are highly expressed in the hippocampus, a region of the brain believed to have an important function in certain forms of learning and memory. In this study, we clarified the mechanism underlying the cognitive impairment that develops during MDMA withdrawal from the standpoint of the cannabinoid CB(1) receptors. Mice were administered MDMA (10 mg/kg, i.p.) once a day for 7 days. On the 7th day of withdrawal, a novel object recognition task was performed and the amount of cannabinoid CB(1) receptor protein was measured with western blotting. Recognition performance was impaired on the 7th day of withdrawal. This impairment was blocked by AM251, a cannabinoid CB(1) receptor antagonist, administered 30 min before the training trial or co-administered with MDMA. At this time, the level of cannabinoid CB(1) receptor protein increased significantly in the hippocampus but not the prefrontal cortex or striatum. This increase of CB(1) receptor protein in the hippocampus was also blocked by the co-administration of AM251. Furthermore, CB(1) receptor knockout mice showed no impairment of recognition performance on the withdrawal from MDMA. The impairment of recognition memory during withdrawal from MDMA may result from the activation of cannabinoid CB(1) receptors in the hippocampus.

  15. AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists.

    Science.gov (United States)

    Moody, Terry W; Tashakkori, Nicole; Mantey, Samuel A; Moreno, Paola; Ramos-Alvarez, Irene; Leopoldo, Marcello; Jensen, Robert T

    2017-01-01

    While peptide antagonists for the gastrin-releasing peptide receptor (BB2R), neuromedin B receptor (BB1R), and bombesin (BB) receptor subtype-3 (BRS-3) exist, there is a need to develop non-peptide small molecule inhibitors for all three BBR. The BB agonist (BA)1 binds with high affinity to the BB1R, BB2R, and BRS-3. In this communication, small molecule BBR antagonists were evaluated using human lung cancer cells. AM-37 and ST-36 inhibited binding to human BB1R, BB2R, and BRS-3 with similar affinity (Ki = 1.4-10.8 µM). AM-13 and AM-14 were approximately an order of magnitude less potent than AM-37 and ST-36. The ability of BA1 to elevate cytosolic Ca(2+) in human lung cancer cells transfected with BB1R, BB2R, and BRS-3 was antagonized by AM-37 and ST-36. BA1 increased tyrosine phosphorylation of the EGFR and ERK in lung cancer cells, which was blocked by AM-37 and ST-36. AM-37 and ST-36 reduced the growth of lung cancer cells that have BBR. The results indicate that AM-37 and ST-36 function as small molecule BB receptor antagonists.

  16. Churg-Strauss syndrome associated with leukotriene receptor antagonists (LTRA).

    Science.gov (United States)

    Cuchacovich, R; Justiniano, M; Espinoza, L R

    2007-10-01

    Churg-Strauss syndrome (CSS) is a rare vasculitic disorder that generally occurs in patients with bronchial asthma. CSS is being increasingly recognized in asthmatic patients treated with leukotriene receptor antagonists. However, the nature of this relationship remains to be elucidated. The present report describes three asthmatic patients who developed clinical manifestations highly suggestive of CSS, although one patient lacked the presence of eosinophilia. The patient, however, exhibited biopsy-proven cutaneous necrotizing vasculitis, which improved after withdrawal of montelukast. The second patient presented with systemic constitutional signs including fever, malaise, arthralgias, clinical jaundice, peripheral blood eosinophilia, and biopsy-proven eosinophilic hepatitis. The third patient also had circulating eosinophilia, scleritis, and arthritis. All patients improved after discontinuation of the leukotriene receptor antagonist (montelukast).

  17. Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.

    Science.gov (United States)

    Robertson, D W; Lacefield, W B; Bloomquist, W; Pfeifer, W; Simon, R L; Cohen, M L

    1992-01-24

    Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

  18. Mineralocorticoid receptor antagonists: emerging roles in cardiovascular medicine

    OpenAIRE

    Funder JW

    2013-01-01

    John W FunderPrince Henry's Institute, Clayton, Victoria, AustraliaAbstract: Spironolactone was first developed over 50 years ago as a potent mineralocorticoid receptor (MR) antagonist with undesirable side effects; it was followed a decade ago by eplerenone, which is less potent but much more MR-specific. From a marginal role as a potassium-sparing diuretic, spironolactone was shown to be an extraordinarily effective adjunctive agent in the treatment of progressive heart failure, as ...

  19. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    Science.gov (United States)

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  20. A synthetic peptide derivative that is a cholecystokinin receptor antagonist.

    Science.gov (United States)

    Lignon, M F; Galas, M C; Rodriguez, M; Laur, J; Aumelas, A; Martinez, J

    1987-05-25

    So far, there are no known peptidic effective receptor antagonists of both peripheral and central effects of cholecystokinin (CCK). Here, we describe a synthetic peptide derivative of CCK, t-butyloxycarbonyl-Tyr(SO3-)-Met-Gly-D-Trp-Nle-Asp 2-phenylethyl ester 1 (where Nle is norleucine), which is a potent CCK receptor antagonist. In rat and guinea pig dispersed pancreatic acini, this peptide derivative did not alter amylase secretion, but was able to antagonize the stimulation caused by cholecystokinin-related agonists. It caused a parallel rightward shift in the dose-response curve for the stimulation of amylase secretion with half-maximal inhibition of CCK-8-stimulated amylase release at a concentration of about 0.1 microM. Compound 1 was able to inhibit the binding of labeled CCK-9 (the C-terminal nonapeptide of CCK) to rat and guinea pig pancreatic acini (IC50 = 5 X 10(-8) M) as well as to guinea pig cerebral cortical membranes (IC50 = 5 X 10(-7) M). These results indicate that Compound 1 is a potent competitive CCK receptor antagonist.

  1. Discovery of dopamine D₄ receptor antagonists with planar chirality.

    Science.gov (United States)

    Sanna, Fabrizio; Ortner, Birgit; Hübner, Harald; Löber, Stefan; Tschammer, Nuska; Gmeiner, Peter

    2013-04-01

    Employing the D4 selective phenylpiperazine 2 as a lead compound, planar chiral analogs with paracyclophane substructure were synthesized and evaluated for their ability to bind and activate dopamine receptors. The study revealed that the introduction of a [2.2]paracyclophane moiety is tolerated by dopamine receptors of the D2 family. Subtype selectivity for D4 and ligand efficacy depend on the absolute configuration of the test compounds. Whereas the achiral single-layered lead 2 and the double-layered paracyclophane (R)-3 showed partial agonist properties, the enantiomer (S)-3 behaved as a neutral antagonist.

  2. Estrogen Receptor Agonists and Antagonists in the Yeast Estrogen Bioassay.

    Science.gov (United States)

    Wang, Si; Bovee, Toine F H

    2016-01-01

    Cell-based bioassays can be used to predict the eventual biological activity of a substance on a living organism. In vitro reporter gene bioassays are based on recombinant vertebrate cell lines or yeast strains and especially the latter are easy-to-handle, cheap, and fast. Moreover, yeast cells do not express estrogen, androgen, progesterone or glucocorticoid receptors, and are thus powerful tools in the development of specific reporter gene systems that are devoid of crosstalk from other hormone pathways. This chapter describes our experience with an in-house developed RIKILT yeast estrogen bioassay for testing estrogen receptor agonists and antagonists, focusing on the applicability of the latter.

  3. Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.

    Science.gov (United States)

    Bonaventura, Jordi; Navarro, Gemma; Casadó-Anguera, Verònica; Azdad, Karima; Rea, William; Moreno, Estefanía; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I; Lluís, Carme; Cortés, Antoni; Volkow, Nora D; Schiffmann, Serge N; Ferré, Sergi; Casadó, Vicent

    2015-07-07

    Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.

  4. Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

    Energy Technology Data Exchange (ETDEWEB)

    Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

    2014-06-15

    Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

  5. NMDA receptor antagonists extend the sensitive period for imprinting.

    Science.gov (United States)

    Parsons, C H; Rogers, L J

    2000-03-01

    Filial imprinting in the domestic chick occurs during a sensitive period of development. The exact timing of this period can vary according to the methods used to measure imprinting. Using our imprinting paradigm, we have shown that normal, dark-reared chicks lose the ability to imprint after the second day post-hatching. Further, we reported that chicks treated 10 h after hatching with a mixture of the noncompetitive NMDA receptor antagonist ketamine (55 mg/kg) and the alpha(2)-adrenergic receptor agonist xylazine (6 mg/kg) were able to imprint on day 8 after hatching, whereas controls treated with saline did not imprint. We now show that the effect of the ketamine-xylazine mixture can be mimicked by treating chicks with ketamine alone or with another noncompetitive NMDA receptor antagonist, MK-801 (5 mg/kg). Treating chicks with a single dose of ketamine (55 mg/kg) or with a single dose of xylazine (6 mg/kg) failed to produce the effect on the sensitive period. However, prolonging the action of ketamine by treating chicks with two doses of ketamine (at 10 and 12 h after hatching) did allow imprinting on day 8. In contrast, prolonging the action of xylazine had no effect on the sensitive period for imprinting. Chicks treated with MK-801 were also able to imprint on day 8. Thus, we have evidence that the NMDA receptor system is involved in the mechanisms that control the sensitive period for imprinting.

  6. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2015-01-01

    Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one...... for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question...... to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB....

  7. The GHS-R Blocker D-[Lys3] GHRP-6 Serves as CCR5 Chemokine Receptor Antagonist

    Directory of Open Access Journals (Sweden)

    Kalpesh Patel, Vishwa Deep Dixit, Jun Ho Lee, Jie Wan Kim, Eric M. Schaffer, Dzung Nguyen, Dennis D. Taub

    2012-01-01

    Full Text Available [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1α and MIP-1β. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states.

  8. Perivagal antagonist treatment in rats selectively blocks the reflex and afferent responses of vagal lung C fibers to intravenous agonists.

    Science.gov (United States)

    Lin, Yu-Jung; Lin, You Shuei; Lai, Ching Jung; Yuan, Zung Fan; Ruan, Ting; Kou, Yu Ru

    2013-02-01

    The terminals of vagal lung C fibers (VLCFs) express various types of pharmacological receptors that are important to the elicitation of airway reflexes and the development of airway hypersensitivity. We investigated the blockade of the reflex and afferent responses of VLCFs to intravenous injections of agonists using perivagal treatment with antagonists (PAT) targeting the transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors in anesthetized rats. Blockading these responses via perivagal capsaicin treatment (PCT), which blocks the neural conduction of C fibers, was also studied. We used capsaicin, α,β-methylene-ATP, and phenylbiguanide as the agonists, and capsazepine, iso-pyridoxalphosphate-6-azophenyl-2',5'-disulfonate, and tropisetron as the antagonists of transient receptor potential vanilloid 1, P2X, and 5-HT(3) receptors, respectively. We found that each of the PATs abolished the VLCF-mediated reflex apnea evoked by the corresponding agonist, while having no effect on the response to other agonists. Perivagal vehicle treatment failed to produce any such blockade. These blockades had partially recovered at 3 h after removal of the PATs. In contrast, PCT abolished the reflex apneic response to all three agonists. Both PATs and PCT did not affect the myelinated afferent-mediated apneic response to lung inflation. Consistently, our electrophysiological studies revealed that each of the PATs prevented the VLCF responses to the corresponding agonist, but not to any other agonist. PCT inevitably prevented the VLCF responses to all three agonists. Thus these PATs selectively blocked the stimulatory action of corresponding agonists on the VLCF terminals via mechanisms that are distinct from those of PCT. PAT may become a novel intervention for studying the pharmacological modulation of VLCFs.

  9. The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia

    OpenAIRE

    Sauter, Nadine S; Fabienne T Schulthess; Galasso, Ryan; Castellani, Lawrence W.; Maedler, Kathrin

    2008-01-01

    Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for ...

  10. Suvorexant: The first orexin receptor antagonist to treat insomnia

    Directory of Open Access Journals (Sweden)

    Ashok K Dubey

    2015-01-01

    Full Text Available Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.

  11. Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

    Science.gov (United States)

    Roseti, Cristina; Martinello, Katiuscia; Fucile, Sergio; Piccari, Vanessa; Mascia, Addolorata; Di Gennaro, Giancarlo; Quarato, Pier Paolo; Manfredi, Mario; Esposito, Vincenzo; Cantore, Gianpaolo; Arcella, Antonella; Simonato, Michele; Fredholm, Bertil B.; Limatola, Cristina; Miledi, Ricardo; Eusebi, Fabrizio

    2008-01-01

    We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABAA-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced IGABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated IGABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated IGABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABAA-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2–A3 receptors alter the stability of GABAA receptors, which could offer therapeutic opportunities. PMID:18809912

  12. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  13. Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

    Science.gov (United States)

    Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

    Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Cardiovascular effects of selective agonists and antagonists of histamine H3 receptors in the anaesthetized rat.

    Science.gov (United States)

    Coruzzi, G; Gambarelli, E; Bertaccini, G; Timmerman, H

    1995-06-01

    The cardiovascular responses to a series of selective histamine H3 receptor agonists, (R) alpha-methylhistamine, imetit and immepip and selective antagonists, thioperamide, clobenpropit and clophenpropit, were studied in anaesthetized rats. At 0.003-1 mumol/kg i.v. doses, H3 agonists failed to produce any significant change in the basal blood pressure and heart rate. Larger doses of (R) alpha-methylhistamine increased the blood pressure and heart rate and higher doses of imetit caused vasodepressor responses and reduced heart rate, whereas immepip proved virtually inactive. While (R) alpha-methylhistamine-induced effects were not blocked by histamine H1-, H2- and H3-receptor antagonists, they were however reduced by idazoxan and propranolol, which indicates that the mechanisms involved are adrenergic. The effects induced by imetit are not related to histamine H3 receptors but are mediated by indirect (via 5HT3 receptors) cholinergic mechanisms, since these effects were prevented by 1 mg/kg i.v. atropine and by 0.1 mg/kg i.v. ondansetron. Similarly, the H3 antagonists per se failed to change basal cardiovascular function up to 10 mumol/kg i.v. and only at 30 mumol/kg i.v. were marked decreases observed in the blood pressure and heart rate with a significant reduction in the effects of noradrenaline. These data indicate that in anaesthetized rats, histamine H3 receptor activation or blockade has no effect on basal cardiovascular function. The effects recorded after the administration of large doses of (R) alpha-methylhistamine and imetit are clearly unrelated to histamine H3 receptors and should be taken into account when using these compounds as H3 ligands for "in vivo" experiments.

  15. Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.

    Science.gov (United States)

    Ajram, Laura; Begg, Malcolm; Slack, Robert; Cryan, Jenni; Hall, David; Hodgson, Simon; Ford, Alison; Barnes, Ashley; Swieboda, Dawid; Mousnier, Aurelie; Solari, Roberto

    2014-04-15

    The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.

  16. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.

    Directory of Open Access Journals (Sweden)

    Ji Ho Suh

    Full Text Available The androgen receptor (AR surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509 at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC reveals that it inhibits flutamide activation of an AR mutant (ART877A that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR, which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  17. Similarities and Distinctions in Actions of Surface-Directed and Classic Androgen Receptor Antagonists.

    Science.gov (United States)

    Suh, Ji Ho; Chattopadhyay, Arundhati; Sieglaff, Douglas H; Storer Samaniego, Cheryl; Cox, Marc B; Webb, Paul

    2015-01-01

    The androgen receptor (AR) surface-directed antagonist MJC13 inhibits AR function and proliferation of prostate cancer (PC) cells. These effects are related to arrest of an AR/chaperone complex in the cytoplasm. Here, we compared MJC13 and classic AR antagonists such as flutamide and bicalutamide. Microarray analysis and confirmatory qRT-PCR reveals that MJC13 and flutamide inhibit dihydrotestosterone (DHT)-dependent genes in LNCaP PC cells. Both compounds are equally effective on a genome wide basis and as effective as second generation AR antagonists (MDV3100, ARN-509) at selected genes. MJC13 inhibits AR binding to the prostate specific antigen (PSA) promoter more strongly than flutamide, consistent with different mechanisms of action. Examination of efficacy of MJC13 in conditions that reflect aspects castrate resistant prostate cancer (CRPC) reveals that it inhibits flutamide activation of an AR mutant (ART877A) that emerges during flutamide withdrawal syndrome, but displays greatly restricted gene-specific activity in 22Rv1 cells that express a constitutively active truncated AR and is inactive against glucocorticoid receptor (GR), which can co-opt androgen-dependent signaling networks in CRPC. Importantly, MJC13 inhibits AR interactions with SRC2 and β-catenin in the nucleus and, unlike flutamide, strongly inhibits amplification of AR activity obtained with transfected SRC2 and β-catenin. MJC13 also inhibits DHT and β-catenin-enhanced cell division in LNCaP cells. Thus, a surface-directed antagonist can block AR activity in some conditions in which a classic antagonist fails and may display utility in particular forms of CRPC.

  18. Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure.

    Science.gov (United States)

    Moore, Tera D; Nawarskas, James J; Anderson, Joe R

    2003-01-01

    Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post

  19. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant.

    Science.gov (United States)

    Norman, Jessica L; Anderson, Sarah L

    2016-01-01

    Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

  20. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Hui [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Department of Laboratory Medicine, The Affiliated Tenth People' s Hospital, Tongji University, Shanghai 200072 (China); Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China); Wang, Zhanli [College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014 (China); Liang, Huaping, E-mail: huaping_liang@yahoo.com.cn [State Key Laboratory of Trauma, Burns, and Combined Injury, Department 1, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042 (China)

    2010-11-05

    Research highlights: {yields} Evodiamine interacted with the AhR. {yields} Evodiamine inhibited the specific binding of [{sup 3}H]-TCDD to the AhR. {yields} Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K{sub i} value of 28.4 {+-} 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  1. Classification and virtual screening of androgen receptor antagonists.

    Science.gov (United States)

    Li, Jiazhong; Gramatica, Paola

    2010-05-24

    Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

  2. Oral Administration of a Retinoic Acid Receptor Antagonist Reversibly Inhibits Spermatogenesis in Mice

    OpenAIRE

    Chung, Sanny S. W.; Wang, Xiangyuan; Roberts, Shelby S.; Stephen M Griffey; Reczek, Peter R.; Wolgemuth, Debra J.

    2011-01-01

    Meeting men's contraceptive needs, orally administered retinoic acid receptor antagonists represent new lead molecules in developing non-hormonal, reversible male contraceptives without adverse side effects.

  3. Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel , Tracy M. (Vertex Pharm); (Leiden-MC); (USC); (BMS); (UCSD)

    2016-12-07

    CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

  4. Prospective therapeutic agents for obesity: molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists.

    Science.gov (United States)

    Sharma, Mayank Kumar; Murumkar, Prashant R; Kanhed, Ashish M; Giridhar, Rajani; Yadav, Mange Ram

    2014-05-22

    Presently, obesity is one of the major health problems in the developed as well as developing countries due to lack of physical work and increasing sedentary life style. Endocannabinoid system (ECS) and especially cannabinoid 1 (CB1) receptor play a key role in energy homeostasis. Food intake and energy storage is enhanced due to the stimulation of ECS hence, inhibition of ECS by blocking CB1 receptors could be a promising approach in the treatment of obesity. Rimonabant, a diaryl pyrazole was the first potent and selective CB1 receptor antagonist that was introduced into the market in 2006 but was withdrawn in 2008 due to its psychiatric side effects. Researchers all over the world are interested to develop peripherally acting potent and selective CB1 receptor antagonists having a better pharmacokinetic profile and therapeutic index. In this development process, pyrazole ring of rimonabant has been replaced by different bioisosteric scaffolds like pyrrole, imidazole, triazole, pyrazoline, pyridine etc. Variations in substituents around the pyrazole ring have also been done. New strategies were also employed for minimizing the psychiatric side effects by making more polar and less lipophilic antagonists/inverse agonists along with neutral antagonists acting peripherally. It has been observed that some of the peripherally acting compounds do not show adverse effects and could be used as potential leads for the further design of selective CB1 receptor antagonists. Chemical modification strategies used for the development of selective CB1 receptor antagonists are discussed here in this review. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  5. CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice.

    Directory of Open Access Journals (Sweden)

    Lixin Wang

    Full Text Available Corticotropin-releasing factor (CRF signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

  6. Screening and identification of receptor antagonist for shiga toxin from random peptides displayed on filamentous bacteriophages

    Institute of Scientific and Technical Information of China (English)

    韩照中; 苏国富; 黄翠芬

    1999-01-01

    The bacteriophage clones which can bind with shiga toxin B subunit (StxB) and inhibit cytotoxicity of shiga toxin were obtained by using antibody capturing method from a 15-mer random peptide library displayed on the surface of bacteriophage fd. Among them, one peptide encoded by the random DNA region of a selected bacteriophage (A12) was synthesized and tested in vitro and in vivo, where the peptide competed with the receptor of shiga toxin to bind StxB, and inhibited the cytotoxicity and enterotoxicity of shiga toxin. The peptide can also block other apparently unrelated StxB binding bacteriophage (A3), which suggests that there are overlapping StxB interaction sites for those ligands with different sequences. The results provide a demonstration of bacteriophage display to screen peptide ligands for a small and/or unable biotinylated molecule by antibodies-capturing strategy, and take the lead for the development of receptor antagonists for shiga toxin.

  7. Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.

    Science.gov (United States)

    Reilly, Regina M; McDonald, Heath A; Puttfarcken, Pamela S; Joshi, Shailen K; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H; Segreti, Jason A; Neelands, Torben R; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R; Turner, Teresa M; Voight, Eric A; Daanen, Jerome F; Schmidt, Robert G; Gomtsyan, Arthur; Kort, Michael E; Faltynek, Connie R; Kym, Philip R

    2012-08-01

    The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.

  8. Preliminary investigations into triazole derived androgen receptor antagonists.

    Science.gov (United States)

    Altimari, Jarrad M; Niranjan, Birunthi; Risbridger, Gail P; Schweiker, Stephanie S; Lohning, Anna E; Henderson, Luke C

    2014-05-01

    A range of 1,4-substituted-1,2,3-N-phenyltriazoles were synthesized and evaluated as non-steroidal androgen receptor (AR) antagonists. The motivation for this study was to replace the N-phenyl amide portion of small molecule antiandrogens with a 1,2,3-triazole and determine effects, if any, on biological activity. The synthetic methodology presented herein is robust, high yielding and extremely rapid. Using this methodology a series of 17 N-aryl triazoles were synthesized from commercially available starting materials in less than 3h. After preliminary biological screening at 20 and 40 μM, the most promising three compounds were found to display IC50 values of 40-50 μM against androgen dependent (LNCaP) cells and serve as a starting point for further structure-activity investigations. All compounds in this work were the focus of an in silico study to dock the compounds into the human androgen receptor ligand binding domain (hARLBD) and compare their predicted binding affinity with known antiandrogens. A comparison of receptor-ligand interactions for the wild type and T877A mutant AR revealed two novel polar interactions. One with Q738 of the wild type site and the second with the mutated A877 residue.

  9. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  10. Phenylthiophenecarboxamide antagonists of the olfactory receptor co-receptor subunit from a mosquito.

    Directory of Open Access Journals (Sweden)

    Sisi Chen

    Full Text Available Insects detect environmental chemicals using chemosensory receptors, such as the ORs, a family of odorant-gated ion channels. Insect ORs are multimeric complexes of unknown stoichiometry, formed by a common subunit (the odorant receptor co-receptor subunit, Orco and one of many variable subunits that confer odorant specificity. The recent discovery of Orco directed ligands, including both agonists and antagonists, suggests Orco as a promising target for chemical control of insects. In addition to competitively inhibiting OR activation by Orco agonists, several Orco antagonists have been shown to act through a non-competitive mechanism to inhibit OR activation by odorants. We previously identified a series of Orco antagonists, including N-(4-ethylphenyl-2-thiophenecarboxamide (OX1a, previously referred to as OLC20. Here, we explore the chemical space around the OX1a structure to identify more potent Orco antagonists. Cqui\\Orco+Cqui\\Or21, an OR from Culex quinquefasciatus (the Southern House Mosquito that responds to 3-methylindole (skatole and is thought to mediate oviposition behavior, was expressed in Xenopus oocytes and receptor function assayed by two-electrode voltage clamp electrophysiology. 22 structural analogs of OX1a were screened for antagonism of OR activation by an Orco agonist. By varying the moieties decorating the phenyl and thiophene rings, and altering the distance between the rings, we were able to identify antagonists with improved potency. Detailed examination of three of these compounds (N-mesityl-2-thiophenecarboxamide, N-(4-methylbenzyl-2-thiophenecarboxamide and N-(2-ethylphenyl-3-(2-thienyl-2-propenamide demonstrated competitive inhibition of receptor activation by an Orco agonist and non-competitive inhibition of receptor activation by an odorant. The ability to inhibit OR activation by odorants may be a general property of this class of Orco antagonist, suggesting that odorant mediated behaviors can be manipulated

  11. Recent Progress in the Use of Glucagon and Glucagon Receptor Antago-nists in the Treatment of Diabetes Mellitus.

    Science.gov (United States)

    Lotfy, Mohamed; Kalasz, Huba; Szalai, Gyorgy; Singh, Jaipaul; Adeghate, Ernest

    2014-01-01

    Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques.

  12. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2

    DEFF Research Database (Denmark)

    Zweemer, Annelien J M; Bunnik, Julia; Veenhuizen, Margo

    2014-01-01

    The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly be divi...

  13. The discovery of novel human androgen receptor antagonist chemotypes using a combined pharmacophore screening procedure.

    Science.gov (United States)

    Voet, Arnout; Helsen, Christine; Zhang, Kam Y J; Claessens, Frank

    2013-04-01

    Unraveling the mechanisms involved in castration- and therapy-resistant prostate cancer has led to a renewed interest in androgen receptor (AR)-targeted therapeutics. Anti-androgens that block the activity of the AR therefore remain a valid therapeutic option. However, they must be more effective than, or display a distinct mechanism of action or binding mode from those of bicalutamide and hydroxyflutamide, which are currently in clinical use. For that reason, the second-generation anti-androgen MDV3100 was developed. MDV3100, however, shares its 4-cyano-3-(trifluoromethyl)phenyl group with bicalutamide and hydroxyflutamide required for binding to the AR. In this work, we used a combined strategy to find new antagonist structures distinct from the 4-cyano-3-(trifluoromethyl)phenyl group to avoid cross-resistance for these compounds and to find structures without agonist activity on mutant ARs (AR W741C and AR T877A). We found two novel chemotypes with AR-antagonistic activity (IC(50): 3-6 μM) by virtual screening and confirmed their biological activity in an androgen-responsive reporter assay. The design of our computational approach was validated by the observation of strongly decreased or absence of agonistic activity on the two mutant ARs. Further structural derivatization to optimize the potency of these compounds can render these chemotypes into very promising, alternative AR antagonists for prostate cancer therapy.

  14. Implementation of a fluorescence-based screening assay identifies histamine H3 receptor antagonists clobenpropit and iodophenpropit as subunit-selective N-methyl-D-aspartate receptor antagonists.

    Science.gov (United States)

    Hansen, Kasper B; Mullasseril, Praseeda; Dawit, Sara; Kurtkaya, Natalie L; Yuan, Hongjie; Vance, Katie M; Orr, Anna G; Kvist, Trine; Ogden, Kevin K; Le, Phuong; Vellano, Kimberly M; Lewis, Iestyn; Kurtkaya, Serdar; Du, Yuhong; Qui, Min; Murphy, T J; Snyder, James P; Bräuner-Osborne, Hans; Traynelis, Stephen F

    2010-06-01

    N-Methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels that mediate a slow, Ca(2+)-permeable component of excitatory synaptic transmission in the central nervous system and play a pivotal role in synaptic plasticity, neuronal development, and several neurological diseases. We describe a fluorescence-based assay that measures NMDA receptor-mediated changes in intracellular calcium in a BHK-21 cell line stably expressing NMDA receptor NR2D with NR1 under the control of a tetracycline-inducible promoter (Tet-On). The assay selectively identifies allosteric modulators by using supramaximal concentrations of glutamate and glycine to minimize detection of competitive antagonists. The assay is validated by successfully identifying known noncompetitive, but not competitive NMDA receptor antagonists among 1800 screened compounds from two small focused libraries, including the commercially available library of pharmacologically active compounds. Hits from the primary screen are validated through a secondary screen that used two-electrode voltage-clamp recordings on recombinant NMDA receptors expressed in Xenopus laevis oocytes. This strategy identified several novel modulators of NMDA receptor function, including the histamine H3 receptor antagonists clobenpropit and iodophenpropit, as well as the vanilloid receptor transient receptor potential cation channel, subfamily V, member 1 (TRPV1) antagonist capsazepine. These compounds are noncompetitive antagonists and the histamine H3 receptor ligand showed submicromolar potency at NR1/NR2B NMDA receptors, which raises the possibility that compounds can be developed that act with high potency on both glutamate and histamine receptor systems simultaneously. Furthermore, it is possible that some actions attributed to histamine H3 receptor inhibition in vivo may also involve NMDA receptor antagonism.

  15. Histamine and histamine receptor antagonists in cancer biology.

    Science.gov (United States)

    Blaya, Bruno; Nicolau-Galmés, Francesca; Jangi, Shawkat M; Ortega-Martínez, Idoia; Alonso-Tejerina, Erika; Burgos-Bretones, Juan; Pérez-Yarza, Gorka; Asumendi, Aintzane; Boyano, María D

    2010-07-01

    Histamine has been demonstrated to be involved in cell proliferation, embryonic development, and tumour growth. These various biological effects are mediated through the activation of specific histamine receptors (H1, H2, H3, and H4) that differ in their tissue expression patterns and functions. Although many in vitro and in vivo studies of the modulatory roles of histamine in tumour development and metastasis have been reported, the effect of histamine in the progression of some types of tumours remains controversial; however, recent findings on the role of histamine in the immune system have shed new light on this question. This review focuses on the recent advances in understanding the roles of histamine and its receptors in tumour biology. We report our recent observations of the anti-tumoural effect of H1 histamine antagonists on experimental and human melanomas. We have found that in spite of exogenous histamine stimulated human melanoma cell proliferation, clonogenic ability and migration activity in a dose-dependent manner, the melanoma tumour growth was not modulated by in vivo histamine treatment. On the contrary, terfenadine-treatment in vitro induced melanoma cell death by apoptosis and in vivo terfenadine treatment significantly inhibited tumour growth in murine models. These observations increase our understanding of cancer biology and may inspire novel anticancer therapeutic strategies.

  16. Montelukast: More than a Cysteinyl Leukotriene Receptor Antagonist?

    Directory of Open Access Journals (Sweden)

    Gregory R. Tintinger

    2010-01-01

    Full Text Available The prototype cysteinyl leukotriene receptor antagonist, montelukast, is generally considered to have a niche application in the therapy of exercise- and aspirin-induced asthma. It is also used as add-on therapy in patients whose asthma is poorly controlled with inhaled corticosteroid monotherapy, or with the combination of a long-acting β(2-agonist and an inhaled corticosteroid. Recently, however, montelukast has been reported to possess secondary anti-inflammatory properties, apparently unrelated to conventional antagonism of cysteinyl leukotriene receptors. These novel activities enable montelukast to target eosinophils, monocytes, and, in particular, the corticosteroid-insensitive neutrophil, suggesting that this agent may have a broader spectrum of anti-inflammatory activities than originally thought. If so, montelukast is potentially useful in the chemotherapy of intermittent asthma, chronic obstructive pulmonary disease, cystic fibrosis, and viral bronchiolitis, which, to a large extent, involve airway epithelial cell/neutrophil interactions. The primary objective of this mini-review is to present evidence for the cysteinyl leukotrien–independent mechanisms of action of montelukast and their potential clinical relevance.

  17. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

    Directory of Open Access Journals (Sweden)

    Tomoko Asagami

    2011-01-01

    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  18. Development of selective agonists and antagonists of P2Y receptors

    OpenAIRE

    2008-01-01

    Although elucidation of the medicinal chemistry of agonists and antagonists of the P2Y receptors has lagged behind that of many other members of group A G protein-coupled receptors, detailed qualitative and quantitative structure–activity relationships (SARs) were recently constructed for several of the subtypes. Agonists selective for P2Y1, P2Y2, and P2Y6 receptors and nucleotide antagonists selective for P2Y1 and P2Y12 receptors are now known. Selective nonnucleotide antagonists were report...

  19. Dopamine D(3) receptor antagonists: The quest for a potentially selective PET ligand. Part two: Lead optimization.

    Science.gov (United States)

    Micheli, Fabrizio; Holmes, Ian; Arista, Luca; Bonanomi, Giorgio; Braggio, Simone; Cardullo, Francesca; Di Fabio, Romano; Donati, Daniele; Gentile, Gabriella; Hamprecht, Dieter; Terreni, Silvia; Heidbreder, Christian; Savoia, Chiara; Griffante, Cristiana; Worby, Angela

    2009-08-01

    The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.

  20. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; Lażewska, Dorota; Adem, Abdu; Kieć-Kononowicz, Katarzyna

    2014-06-01

    To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

  1. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    , in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-ylpropoxyphenylmethanol, and its (S-enantiomer (4 significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R-enantiomer (3 in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

  2. Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists.

    Science.gov (United States)

    He, Shao-Heng; Xie, Hua; Fu, Yi-Ling

    2005-03-01

    The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

  3. Influence of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rat.

    Science.gov (United States)

    Farzin, D; Attarzadeh, M

    2000-09-15

    The effects of different histamine receptor agonists and antagonists on apomorphine-induced licking behavior in rats were investigated. Subcutaneous (s.c.) injection of various doses of apomorphine (0. 125-1.25 mg/kg) induced licking. The licking response was counted by direct observation and recorded for a 75-min period. Intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of the histamine H(1) or H(2) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 and 100 microg per rat), or dimaprit (10 and 15 mg/kg, i.p.), respectively, potentiated apomorphine-induced licking, while the histamine H(3) receptor agonist, imetit (5 and 10 mg/kg, i.p.), reduced the licking response induced by apomorphine. Pretreatment with various histamine receptor antagonists, dexchlorpheniramine (30 and 40 mg/kg, i.p.), diphenhydramine (20, 30 and 40 mg/kg, i.p.), famotidine (30 and 40 mg/kg, s.c.) and ranitidine (20, 30 and 40 mg/kg), reduced apomorphine-induced licking, while thioperamide (5 and 10 mg/kg, i.p.) potentiated the apomorphine effect. The effects of HTMT and dimaprit were blocked by dexchlorpheniramine (20 mg/kg, i.p.) and famotidine (20 mg/kg, s.c.), respectively. The inhibitory effect elicited by imetit on apomorphine-induced licking behavior was also abolished in animals treated with thioperamide (2.5 mg/kg, i.p.). The results suggest that histaminergic mechanisms may be involved in the modulation of apomorphine-induced licking behavior.

  4. [Effects of the histamine H2 receptor antagonist roxatidine acetate on stomach and liver alcohol dehydrogenase and serum alcohol level].

    Science.gov (United States)

    Beil, W; Sewing, K F

    1993-11-01

    Some histamine-H2-receptor antagonists block gastric first-pass metabolism of ethanol and lead to increased blood alcohol concentrations after ingestion of a low dose (0.15 and 0.3 g/kg) of alcohol. To investigate whether the histamine-H2-receptor antagonist roxatidine acetate has a similar effect, we administered a low dose (0.3 g/kg) of ethanol to eleven volunteers before and after seven days treatment with roxatidine acetate (150 mg once daily). No effect of the drug on mean peak serum alcohol concentrations or on areas under the serum alcohol curves was found. In vitro, roxatidine acetate and its active metabolite roxatidine had almost no effect on guinea-pig gastric alcohol dehydrogenase activity. We conclude that roxatidine acetate does not block gastric first-pass metabolism of ethanol and can be considered as a safe histamine-H2-receptor antagonist in individuals who do not refrain from alcohol consumption under treatment for gastric or duodenal ulcer disease.

  5. Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

    OpenAIRE

    2013-01-01

    Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14–35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-met...

  6. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R;

    2010-01-01

    studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin......During migraine, trigeminal nerves may release calcitonin gene-related peptide (CGRP), inducing cranial vasodilatation and central nociception; hence, trigeminal inhibition or blockade of craniovascular CGRP receptors may prevent this vasodilatation and abort migraine headache. Several preclinical...

  7. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, and its (S)-enantiomer (4) significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R)-enantiomer (3) in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and

  8. Endothelin receptor B antagonists decrease glioma cell viability independently of their cognate receptor

    Directory of Open Access Journals (Sweden)

    Patterson Paul H

    2008-11-01

    Full Text Available Abstract Background Endothelin receptor antagonists inhibit the progression of many cancers, but research into their influence on glioma has been limited. Methods We treated glioma cell lines, LN-229 and SW1088, and melanoma cell lines, A375 and WM35, with two endothelin receptor type B (ETRB-specific antagonists, A-192621 and BQ788, and quantified viable cells by the capacity of their intracellular esterases to convert non-fluorescent calcein AM into green-fluorescent calcein. We assessed cell proliferation by labeling cells with carboxyfluorescein diacetate succinimidyl ester and quantifying the fluorescence by FACS analysis. We also examined the cell cycle status using BrdU/propidium iodide double staining and FACS analysis. We evaluated changes in gene expression by microarray analysis following treatment with A-192621 in glioma cells. We examined the role of ETRB by reducing its expression level using small interfering RNA (siRNA. Results We report that two ETRB-specific antagonists, A-192621 and BQ788, reduce the number of viable cells in two glioma cell lines in a dose- and time-dependent manner. We describe similar results for two melanoma cell lines. The more potent of the two antagonists, A-192621, decreases the mean number of cell divisions at least in part by inducing a G2/M arrest and apoptosis. Microarray analysis of the effects of A-192621 treatment reveals up-regulation of several DNA damage-inducible genes. These results were confirmed by real-time RT-PCR. Importantly, reducing expression of ETRB with siRNAs does not abrogate the effects of either A-192621 or BQ788 in glioma or melanoma cells. Furthermore, BQ123, an endothelin receptor type A (ETRA-specific antagonist, has no effect on cell viability in any of these cell lines, indicating that the ETRB-independent effects on cell viability exhibited by A-192621 and BQ788 are not a result of ETRA inhibition. Conclusion While ETRB antagonists reduce the viability of glioma cells

  9. Blockade of murine T cell activation by antagonists of P2Y6 and P2X7 receptors.

    Science.gov (United States)

    Tsukimoto, Mitsutoshi; Tokunaga, Akihiro; Harada, Hitoshi; Kojima, Shuji

    2009-07-10

    Extracellular nucleotides and their metabolites activate ionotropic P2X and metabotropic P2Y receptors on the surface of various types of cells. Here, we investigated the involvement of P2X and P2Y receptor-mediated signaling in TCR-dependent T cell activation. Murine T cells were activated by stimulation of TCR, and both CD25 expression and interleukin (IL)-2 production were observed in activated T cells. Ecto-nucleotidase apyrase and P2Y6 antagonist MRS2578 significantly blocked the increases of both CD25 expression and IL-2 production, and P2X7 antagonists A438079 and oxidized ATP inhibited IL-2 production rather than CD25 expression, suggesting the involvement of P2Y6 and P2X7 receptors in different processes of T cell activation. MRS2578 also blocked TCR-dependent elevation of cytosolic Ca2+ in T cells. The P2X7 and P2Y6 receptors were expressed in murine CD4 T cells. In conclusion, our results indicate that activation of P2Y6 and P2X7 receptors contributes to T cell activation via TCR.

  10. Rational design of an auxin antagonist of the SCF(TIR1) auxin receptor complex.

    Science.gov (United States)

    Hayashi, Ken-ichiro; Neve, Joshua; Hirose, Masakazu; Kuboki, Atsuhito; Shimada, Yukihisa; Kepinski, Stefan; Nozaki, Hiroshi

    2012-03-16

    The plant hormone auxin is a master regulator of plant growth and development. By regulating rates of cell division and elongation and triggering specific patterning events, indole 3-acetic acid (IAA) regulates almost every aspect of plant development. The perception of auxin involves the formation of a ternary complex consisting of an F-box protein of the TIR1/AFB family of auxin receptors, the auxin molecule, and a member the Aux/IAA family of co-repressor proteins. In this study, we identified a potent auxin antagonist, α-(phenylethyl-2-oxo)-IAA, as a lead compound for TIR1/AFB receptors by in silico virtual screening. This molecule was used as the basis for the development of a more potent TIR1 antagonist, auxinole (α-[2,4-dimethylphenylethyl-2-oxo]-IAA), using a structure-based drug design approach. Auxinole binds TIR1 to block the formation of the TIR1-IAA-Aux/IAA complex and so inhibits auxin-responsive gene expression. Molecular docking analysis indicates that the phenyl ring in auxinole would strongly interact with Phe82 of TIR1, a residue that is crucial for Aux/IAA recognition. Consistent with this predicted mode of action, auxinole competitively inhibits various auxin responses in planta. Additionally, auxinole blocks auxin responses of the moss Physcomitrella patens, suggesting activity over a broad range of species. Our works not only substantiates the utility of chemical tools for plant biology but also demonstrates a new class of small molecule inhibitor of protein-protein interactions common to mechanisms of perception of other plant hormones, such as jasmonate, gibberellin, and abscisic acid.

  11. Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

    Science.gov (United States)

    Ammazzalorso, Alessandra; Carrieri, Antonio; Verginelli, Fabio; Bruno, Isabella; Carbonara, Giuseppe; D'Angelo, Alessandra; De Filippis, Barbara; Fantacuzzi, Marialuigia; Florio, Rosalba; Fracchiolla, Giuseppe; Giampietro, Letizia; Giancristofaro, Antonella; Maccallini, Cristina; Cama, Alessandro; Amoroso, Rosa

    2016-05-23

    Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding

    DEFF Research Database (Denmark)

    Hansen, Mathilde Johanne Kaas; Olsen, Johan Gotthardt; Bernichtein, Sophie;

    2011-01-01

    H than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ~6.8 making histidine residues obvious candidates for examination....... From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity...... and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure...

  13. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.

    Science.gov (United States)

    Kalinowski, Leszek; Matys, Tomasz; Chabielska, Ewa; Buczko, Włodzimierz; Malinski, Tadeusz

    2002-10-01

    This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT1)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT1-receptor antagonist-stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT1-receptor antagonists on platelet adhesion to collagen and thromboxane A2 analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 micro mol/L, which was attenuated by NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. The angiotensin II AT1-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT1-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N(G)-nitro-L-arginine methyl ester. Neither the AT2 receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A2/prostaglandin H2 receptor antagonist SQ29,548 had any effect on angiotensin II AT1-receptor antagonist-stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT1-receptor antagonists.

  14. The NK-1 Receptor Antagonist L-732,138 Induces Apoptosis and Counteracts Substance P-Related Mitogenesis in Human Melanoma Cell Lines

    Energy Technology Data Exchange (ETDEWEB)

    Muñoz, Miguel, E-mail: mmunoz@cica.es; Rosso, Marisa; González-Ortega, Ana [Research Laboratory on Neuropeptides, Virgen del Rocío University Hospital, Sevilla (Spain); Coveñas, Rafael [Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems (Laboratory 14), Salamanca (Spain)

    2010-04-20

    It has been recently demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition in human melanoma cells, respectively. However, the antitumor action of the NK-1 receptor antagonist L-732,138 on such cells is unknown. The aim of this study was to demonstrate an antitumor action of L-732,138 against three human melanoma cell lines (COLO 858, MEL HO, COLO 679). We found that L-732,138 elicits cell growth inhibition in a concentration dependent manner in the melanoma cells studied. Moreover, L-732,138 blocks SP mitogen stimulation. The specific antitumor action of L-732,138 occurred through the NK-1 receptor and melanoma cell death was by apoptosis. These findings indicate that the NK-1 receptor antagonist L-732,138 could be a new antitumor agent in the treatment of human melanoma.

  15. Iontophoresis of endothelin receptor antagonists in rats and men.

    Directory of Open Access Journals (Sweden)

    Matthieu Roustit

    Full Text Available INTRODUCTION: The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis. METHODS: Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA was subsequently performed on the forearm skin of healthy men (n = 5. RESULTS: In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20 were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01. In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans. CONCLUSIONS: This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

  16. Modulation of glutamate transport and receptor binding by glutamate receptor antagonists in EAE rat brain.

    Science.gov (United States)

    Sulkowski, Grzegorz; Dąbrowska-Bouta, Beata; Salińska, Elżbieta; Strużyńska, Lidia

    2014-01-01

    The etiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. The antagonists of group I metabotropic glutamate receptors (mGluRs), including LY 367385 and MPEP, did not exert any effect on the examined parameters. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE.

  17. Effects of GABA receptor antagonists on thresholds of P23H rat retinal ganglion cells to electrical stimulation of the retina

    Science.gov (United States)

    Jensen, Ralph J.; Rizzo, Joseph F., III

    2011-06-01

    An electronic retinal prosthesis may provide useful vision for patients suffering from retinitis pigmentosa (RP). In animal models of RP, the amount of current needed to activate retinal ganglion cells (RGCs) is higher than in normal, healthy retinas. In this study, we sought to reduce the stimulation thresholds of RGCs in a degenerate rat model (P23H-line 1) by blocking GABA receptor mediated inhibition in the retina. We examined the effects of TPMPA, a GABAC receptor antagonist, and SR95531, a GABAA receptor antagonist, on the electrically evoked responses of RGCs to biphasic current pulses delivered to the subretinal surface through a 400 µm diameter electrode. Both TPMPA and SR95531 reduced the stimulation thresholds of ON-center RGCs on average by 15% and 20% respectively. Co-application of the two GABA receptor antagonists had the greatest effect, on average reducing stimulation thresholds by 32%. In addition, co-application of the two GABA receptor antagonists increased the magnitude of the electrically evoked responses on average three-fold. Neither TPMPA nor SR95531, applied alone or in combination, had consistent effects on the stimulation thresholds of OFF-center RGCs. We suggest that the effects of the GABA receptor antagonists on ON-center RGCs may be attributable to blockage of GABA receptors on the axon terminals of ON bipolar cells.

  18. ASSESSMENT OF EFFICACY OF LEUKOTRIENE RECEPTOR ANTAGONISTS IN THERAPY OF BRONCHIAL ASTHMA IN CHILDREN

    Directory of Open Access Journals (Sweden)

    Yu.G. Levina

    2009-01-01

    Full Text Available The article provides data regarding the clinical efficacy and safety of leukotriene receptor antagonists in treatment of bronchial asthma in children. The only representative of this group that is allowed in Russia for treatment of children over 6 years of age is Montelukast. Approval of new 4 mg dosage of Montelukast for children from 2 years of age is expected in Russia in July 2009. Leukotriene receptor antagonists have a high safety profile and can be used as an alternative first-line therapy for persistent asthma.Key words: leukotriene receptor antagonists, montelukast, bronchial asthma, children.

  19. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs

    Indian Academy of Sciences (India)

    Miguel Muñoz; Rafael Coveñas; Francisco Esteban; Maximino Redondo

    2015-06-01

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less well-known compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs.

  20. Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening.

    Science.gov (United States)

    Wang, Xing; Zhang, Yuxin; Liu, Qing; Ai, Zhixin; Zhang, Yanling; Xiang, Yuhong; Qiao, Yanjiang

    2016-03-16

    Endothelin-1 receptors (ETAR and ETBR) act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA) was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

  1. Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

    Directory of Open Access Journals (Sweden)

    Xing Wang

    2016-03-01

    Full Text Available Endothelin-1 receptors (ETAR and ETBR act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

  2. The NK1 receptor antagonist L822429 reduces heroin reinforcement.

    Science.gov (United States)

    Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

    2013-05-01

    Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects.

  3. Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Chong Chen; Shi-Hai Xia; Hong Chen; Xiao-Hong Li

    2008-01-01

    Acute pancreatitis (AP) causes release of plateletactivating factor (PAF),which induces systemic effects that contribute to circulatory disturbances and multiple organ failure.PAF is a cell surface secretion of bioactive lipid,which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R).Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP.PAF has also been implicated as a key mediator in the progression of severe AP,which can lead to complications and unacceptably high mortality rates.Several classes of PAF-RA show PAFRAs significant local and systemic effects on reducing inflammatory changes.As a preventive treatment,PAF-RA could block a series of PAF-mediatedinflammatory injury and thus improve the prognosis of AR This review introduces the important role of PAF-RA in the treatment of AP.

  4. Effects of the nonpeptide V(1) vasopressin receptor antagonist SR49059 in hypertensive patients.

    Science.gov (United States)

    Thibonnier, M; Kilani, A; Rahman, M; DiBlasi, T P; Warner, K; Smith, M C; Leenhardt, A F; Brouard, R

    1999-12-01

    We assessed the clinical and pharmacological profile of the orally active V(1) vascular vasopressin (AVP) receptor nonpeptide antagonist SR49059 (SR) during the osmotic stimulation of AVP release in hypertensive patients. In a double-blind crossover-versus-placebo study, 24 untreated stage I or II essential hypertensive patients (12 whites and 12 blacks) received a single 300 mg oral dose of SR 2 hours before the stimulation of AVP secretion with a 5% hypertonic saline infusion. Hemodynamic, humoral, and hormonal parameters were monitored for up to 28 hours after drug administration. SR did not alter blood pressure or heart rate before the saline infusion and did not reduce the blood pressure increment induced by the hypertonic saline infusion. However, the blood pressure peak at the end of the hypertonic saline infusion was slightly lower in the presence of SR (P=0.04). Heart rate was significantly faster between 4 and 6 hours after SR administration (P=0.02). The rise in plasma sodium and osmolality triggered by the saline infusion was not modified by SR, but AVP release was slightly greater in the presence of SR (P<0.0003). AVP-induced aggregation of blood platelets in vitro was significantly reduced by SR, with a peak effect 2 hours after drug administration that coincided with the SR peak plasma concentration. Plasma renin activity and aldosterone before and after the saline infusion were not modified by SR. Urine volume and osmolality were not altered by SR administration. SR effects were similar in the 2 ethnic groups as well as in salt-sensitive versus salt-resistant patients. In a situation of AVP osmotic release and volume expansion in hypertensive patients, a single oral dose of the V(1) vascular AVP receptor nonpeptide antagonist SR49059, which is able to block AVP-induced platelet aggregation, exerts a transient vasodilation effect that is not associated with a sustained blood pressure reduction. SR49059 is a pure V(1) vascular receptor antagonist that

  5. Acute-phase responses in transgenic mice with CNS overexpression of IL-1 receptor antagonist.

    Science.gov (United States)

    Lundkvist, J; Sundgren-Andersson, A K; Tingsborg, S; Ostlund, P; Engfors, C; Alheim, K; Bartfai, T; Iverfeldt, K; Schultzberg, M

    1999-03-01

    The interleukin-1 (IL-1) receptor antagonist (IL-1ra) is an endogenous antagonist that blocks the effects of the proinflammatory cytokines IL-1alpha and IL-1beta by occupying the type I IL-1 receptor. Here we describe transgenic mice with astrocyte-directed overexpression of the human secreted IL-1ra (hsIL-1ra) under the control of the murine glial fibrillary acidic protein (GFAP) promoter. Two GFAP-hsIL-1ra strains have been generated and characterized further: GILRA2 and GILRA4. These strains show a brain-specific expression of the hsIL-1ra at the mRNA and protein levels. The hsIL-1ra protein was approximated to approximately 50 ng/brain in cytosolic fractions of whole brain homogenates, with no differences between male and female mice or between the two strains. Furthermore, the protein is secreted, inasmuch as the concentration of hsIL-1ra in the cerebrospinal fluid was 13 (GILRA2) to 28 (GILRA4) times higher in the transgenic mice than in the control animals. To characterize the transgenic phenotype, GILRA mice and nontransgenic controls were injected with recombinant human IL-1beta (central injection) or lipopolysaccharide (LPS, peripheral injection). The febrile response elicited by IL-1beta (50 ng/mouse icv) was abolished in hsIL-1ra-overexpressing animals, suggesting that the central IL-1 receptors were occupied by antagonist. The peripheral LPS injection (25 micrograms/kg ip) triggered a fever in overexpressing and control animals. Moreover, no differences were found in LPS-induced (100 and 1,000 micrograms/kg ip; 1 and 6 h after injection) IL-1beta and IL-6 serum levels between GILRA and wild-type mice. On the basis of these results, we suggest that binding of central IL-1 to central IL-1 receptors is not important in LPS-induced fever or LPS-induced IL-1beta and IL-6 plasma levels.

  6. INCREASED PLASMA-CONCENTRATIONS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST IN NEONATAL SEPSIS

    NARCIS (Netherlands)

    DEBONT, ESJM; DELEIJ, LHFM; OKKEN, A; BAARSMA, R; KIMPEN, JLL

    Newborns are prone to severe infections and sepsis. Cytokines such as tumor necrosis factor-alpha and IL-1 beta play a major role in the initiation of the host response to infections. IL-1 receptor antagonist (IL-1ra) is a naturally occurring antagonist of IL-1 beta. we hypothesized that low IL-1ra

  7. Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

    Science.gov (United States)

    Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

    2015-11-01

    In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W

    1998-04-01

    It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. Furthermore, because glutamate receptor antagonists, particularly those acting on NMDA receptors, protect effectively in the induction of kindling, it was suggested that they may have utility in epilepsy prophylaxis, for example, after head trauma. However, first clinical trials with competitive and uncompetitive NMDA receptor antagonists in patients with partial (focal) seizures, showed that these drugs lack convincing anticonvulsant activity but induce severe neurotoxic adverse effects in doses which were well tolerated in healthy volunteers. Interestingly, the only animal model which predicted the unfavorable clinical activity of competitive NMDA antagonists in patients with chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating that this model should be used in the search for more effective and less toxic glutamate receptor antagonists. In this review, results from a large series of experiments on different categories of glutamate receptor antagonists in fully kindled rats are summarized and discussed. NMDA antagonists, irrespective whether they are competitive, high- or low-affinity uncompetitive, glycine site or polyamine site antagonists, do not counteract focal seizure activity and only weakly, if at all, attenuate propagation to secondarily generalized seizures in this model, indicating that once kindling is established, NMDA receptors are not critical for the expression of

  9. Evaluation of selective NK(1) receptor antagonist CI-1021 in animal models of inflammatory and neuropathic pain.

    Science.gov (United States)

    Gonzalez, M I; Field, M J; Hughes, J; Singh, L

    2000-08-01

    CI-1021 ([(2-benzofuran)-CH(2)OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH (3))Ph) is a selective and competitive neurokinin-1 (NK(1)) receptor antagonist. This study examines its activity in animal models of inflammatory and neuropathic pain. In mice, CI-1021 (1-30 mg/kg, s.c.) dose dependently blocked the development of the late phase of the formalin response with a minimum effective dose (MED) of 3 mg/kg. Two chemically unrelated NK(1) receptor antagonists, CP-99,994 (3-30 mg/kg) and SR 140333 (1-100 mg/kg), also dose dependently blocked the late phase, with respective MEDs of 3 and 10 mg/kg. PD 156982, a NK(1) receptor antagonist with poor central nervous system penetration, failed to have any effect. However, when administered i. c.v., it selectively blocked the late phase of the formalin response. Chronic constrictive injury (CCI) to a sciatic nerve in the rat induced spontaneous pain, thermal and mechanical hyperalgesia, and cold, dynamic, and static allodynia. CI-1021 (10-100 mg/kg) and morphine (3 mg/kg) blocked all the responses except dynamic allodynia. Carbamazepine (100 mg/kg) was weakly effective against all the responses. Once daily administration of morphine (3 mg/kg, s. c.) in CCI rats led to the development of tolerance within 6 days. Similar administration of CI-1021 (100 mg/kg, s.c.) for up to 10 days did not induce tolerance. Moreover, the morphine tolerance failed to cross-generalize to CI-1021. CI-1021 blocked the CCI-induced hypersensitivity in the guinea pig, with a MED of 0.1 mg/kg, p.o. CI-1021 (10-100 mg/kg, s.c.) did not show sedative/ataxic action in the rat rota-rod test. It is suggested that NK(1) receptor antagonists possess a superior side effect profile to carbamazepine and morphine and may have a therapeutic use for the treatment of inflammatory and neuropathic pain.

  10. Melanin concentrating hormone receptor 1 (MCHR1) antagonists - Still a viable approach for obesity treatment?

    DEFF Research Database (Denmark)

    Högberg, T.; Frimurer, T.M.; Sasmal, P.K.

    2012-01-01

    Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes...

  11. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction : integrating evidence into clinical practice

    NARCIS (Netherlands)

    Zannad, Faiez; Stough, Wendy Gattis; Rossignol, Patrick; Bauersachs, Johann; McMurray, John J. V.; Swedberg, Karl; Struthers, Allan D.; Voors, Adriaan A.; Ruilope, Luis M.; Bakris, George L.; O'Connor, Christopher M.; Gheorghiade, Mihai; Mentz, Robert J.; Cohen-Solal, Alain; Maggioni, Aldo P.; Beygui, Farzin; Filippatos, Gerasimos S.; Massy, Ziad A.; Pathak, Atul; Pina, Ileana L.; Sabbah, Hani N.; Sica, Domenic A.; Tavazzi, Luigi; Pitt, Bertram

    2012-01-01

    Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HFREF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These

  12. Therapeutic potential of CRF receptor antagonists: a gut-brain perspective.

    Science.gov (United States)

    Heinrichs, S C; Taché, Y

    2001-04-01

    Activation of the corticotropin-releasing factor (CRF) family of neuropeptide receptors in the brain and periphery appears to mediate stress-related changes in a variety of physiological and functional domains. Comparative pharmacology of CRF receptor agonists suggests that CRF, urocortin, sauvagine and urotensin consistently mimic, and conversely peptide CRF receptor antagonists lessen, the functional consequences of stressor exposure. Together with the development of novel non-peptide CRF receptor antagonists, a growing number of CRF receptor selective ligands are available to elucidate the neurobiology and physiological role of CRF systems. The present review considers available preclinical evidence as well as results from one Phase II clinical trial which address the hypothesis that CRF receptor antagonists may represent a new option for pharmacotherapy of stress-related disorders.

  13. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia – critical appraisal of suvorexant

    Directory of Open Access Journals (Sweden)

    Norman JL

    2016-07-01

    Full Text Available Jessica L Norman, Sarah L Anderson Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA Abstract: Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of

  14. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  15. Update on leukotriene receptor antagonists in preschool children wheezing disorders

    Directory of Open Access Journals (Sweden)

    Montella Silvia

    2012-06-01

    Full Text Available Abstract Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS, is the cornerstone of asthma management. Since Leukotrienes (LTs are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.

  16. The discovery of the benzazepine class of histamine H3 receptor antagonists.

    Science.gov (United States)

    Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Briggs, Michael A; Calver, Andrew R; Crook, Barry; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heightman, Tom D; Panchal, Terry; Parr, Christopher A; Quashie, Nigel; Steadman, Jon G A; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Takle, Andrew K; Trail, Brenda K; White, Trevor; Witherington, Jason; Worby, Angela; Medhurst, Andrew D

    2013-12-15

    This Letter describes the discovery of a novel series of H3 receptor antagonists. The initial medicinal chemistry strategy focused on deconstructing and simplifying an early screening hit which rapidly led to the discovery of a novel series of H3 receptor antagonists based on the benzazepine core. Employing an H3 driven pharmacodynamic model, the series was then further optimised through to a lead compound that showed robust in vivo functional activity and possessed overall excellent developability properties.

  17. Discovery of antagonists of tick dopamine receptors via chemical library screening and comparative pharmacological analyses.

    Science.gov (United States)

    Ejendal, Karin F K; Meyer, Jason M; Brust, Tarsis F; Avramova, Larisa V; Hill, Catherine A; Watts, Val J

    2012-11-01

    Ticks transmit a wide variety of disease causing pathogens to humans and animals. Considering the global health impact of tick-borne diseases, there is a pressing need to develop new methods for vector control. We are exploring arthropod dopamine receptors as novel targets for insecticide/acaricide development because of their integral roles in neurobiology. Herein, we developed a screening assay for dopamine receptor antagonists to further characterize the pharmacological properties of the two D₁-like dopamine receptors (Isdop1 and Isdop2) identified in the Lyme disease vector, Ixodes scapularis, and develop a screening assay for receptor antagonists. A cell-based, cyclic AMP luciferase reporter assay platform was implemented to screen the LOPAC(1280) small molecule library for Isdop2 receptor antagonists, representing the first reported chemical library screen for any tick G protein-coupled receptor. Screening resulted in the identification of 85 "hit" compounds with antagonist activity at the Isdop2 receptor. Eight of these chemistries were selected for confirmation assays using a direct measurement of cAMP, and the effects on both Isdop1 and Isdop2 were studied for comparison. Each of these eight compounds showed antagonistic activity at both Isdop1 and Isdop2, although differences were observed regarding their relative potencies. Furthermore, comparison of the pharmacological properties of the tick dopamine receptors with that of the AaDOP2 receptor from the yellow fever mosquito and the human dopamine D₁ receptor (hD₁) revealed species-specific pharmacological profiles of these receptors. Compounds influencing dopaminergic functioning, such as the dopamine receptor antagonists discovered here, may provide lead chemistries for discovery of novel acaricides useful for vector control

  18. Conessine, an H3 receptor antagonist, alters behavioral and neurochemical effects of ethanol in mice.

    Science.gov (United States)

    Morais-Silva, Gessynger; Ferreira-Santos, Mariane; Marin, Marcelo T

    2016-05-15

    Ethanol abuse potential is mainly due to its reinforcing properties, crucial in the transition from the recreational to pathological use. These properties are mediated by mesocorticolimbic and nigrostriatal dopaminergic pathways and neuroadaptations in these pathways seem to be responsible for addiction. Both pathways are modulated by other neurotransmitters systems, including neuronal histaminergic system. Among the histamine receptors, H3 receptor stands out due to its role in modulation of histamine and other neurotransmitters release. Thus, histaminergic system, through H3 receptors, may have an important role in ethanol addiction development. Aiming to understand these interactions, conessine, an H3 receptor antagonist, was given to mice subjected to the evaluation of ethanol-induced psychostimulation, ethanol CPP and quantification of norepinephrine, dopamine, serotonin and their metabolites in mesocorticolimbic and nigrostriatal pathways following acute ethanol treatment. Systemic conessine administration exacerbated ethanol effects on locomotor activity. Despite of conessine reinforcing effect on CPP, this drug did not alter acquisition of ethanol CPP. Ethanol treatment affects the serotoninergic neurotransmission in the ventral tegmental area, the dopaminergic neurotransmission in the pre-frontal cortex (PFC) and caudate-putamen nucleus (CPu) and the noradrenergic neurotransmission in the CPu. In the PFC, conessine blocked ethanol effects on dopaminergic and noradrenergic neurotransmission. The blockade of H3 receptors and ethanol seem to interact in the modulation of dopaminergic neurotransmission of nigrostriatal pathway, decreasing dopamine metabolites in substantia nigra. In conclusion, conessine was able to change psychostimulant effect of ethanol, without altering its reinforcing properties. This exacerbation of ethanol-induced psychostimulation would be related to alterations in dopaminergic neurotransmission in the nigrostriatal pathway.

  19. Expression of a glycosylphosphatidylinositol-anchored ligand, growth hormone, blocks receptor signalling.

    Science.gov (United States)

    Guesdon, François; Kaabi, Yahia; Riley, Aiden H; Wilkinson, Ian R; Gray, Colin; James, David C; Artymiuk, Peter J; Sayers, Jon R; Ross, Richard J

    2012-12-01

    We have investigated the interaction between GH (growth hormone) and GHR (GH receptor). We previously demonstrated that a truncated GHR that possesses a transmembrane domain but no cytoplasmic domain blocks receptor signalling. Based on this observation we investigated the impact of tethering the receptor's extracellular domain to the cell surface using a native lipid GPI (glycosylphosphatidylinositol) anchor. We also investigated the effect of tethering GH, the ligand itself, to the cell surface and demonstrated that tethering either the ecGHR (extracellular domain of GHR) or the ligand itself to the cell membrane via a GPI anchor greatly attenuates signalling. To elucidate the mechanism for this antagonist activity, we used confocal microscopy to examine the fluorescently modified ligand and receptor. GH-GPI was expressed on the cell surface and formed inactive receptor complexes that failed to internalize and blocked receptor activation. In conclusion, contrary to expectation, tethering an agonist to the cell surface can generate an inactive hormone receptor complex that fails to internalize.

  20. Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.

    Science.gov (United States)

    Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D

    2010-11-15

    A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

  1. Design, synthesis, and pharmacological characterization of novel, potent NMDA receptor antagonists

    DEFF Research Database (Denmark)

    Conti, Paola; De Amici, Marco; Grazioso, Giovanni

    2004-01-01

    acids were tested at ionotropic and metabotropic glutamate receptors. None of the compounds was active, neither as agonists nor as antagonists, at 1 mM on metabotropic receptors (mGluR1, -2, -4, and -5 expressed in CHO cell lines). Conversely, the pair of stereoisomers 8A/8B showed a remarkable affinity......, antagonist potency, and selectivity for NMDA receptors, when tested on ionotropic glutamate receptors. The affinity of 8A proved to be 5 times higher than that of diastereomer 8B (K(i) values 0.21 and 0.96 microM, respectively). Furthermore, compounds 8A and 8B exhibited a noteworthy anticonvulsant activity...

  2. Effect of ghrelin receptor antagonist on meal patterns in cholecystokinin type 1 receptor null mice.

    Science.gov (United States)

    Lee, Jennifer; Martin, Elizabeth; Paulino, Gabriel; de Lartigue, Guillaume; Raybould, Helen E

    2011-05-03

    Vagal afferent neurons (VAN) express the cholecystokinin (CCK) type 1 receptor (CCK₁R) and, as predicted by the role of CCK in inducing satiation, CCK₁R⁻/⁻ mice ingest larger and longer meals. However, after a short fast, CCK₁R⁻/⁻ mice ingesting high fat (HF) diets initiate feeding earlier than wild-type mice. We hypothesized that the increased drive to eat in CCK₁R⁻/⁻ mice eating HF diet is mediated by ghrelin, a gut peptide that stimulates food intake. The decrease in time to first meal, and the increase in meal size and duration in CCK₁R⁻/⁻ compared to wild-type mice ingesting high fat (HF) diet were reversed by administration of GHSR1a antagonist D-(Lys3)-GHRP-6 (p<0.05). Administration of the GHSR1a antagonist significantly increased expression of the neuropeptide cocaine and amphetamine-regulated transcript (CART) in VAN of HF-fed CCK₁R⁻/⁻ but not wild-type mice. Administration of the GHSR1a antagonist decreased neuronal activity measured by immunoreactivity for fos protein in the nucleus of the solitary tract (NTS) and the arcuate nucleus of both HF-fed wild-type and CCK₁R⁻/⁻ mice. The data show that hyperphagia in CCK₁R⁻/⁻ mice ingesting HF diet is reversed by blockade of the ghrelin receptor, suggesting that in the absence of the CCK₁R, there is an increased ghrelin-dependent drive to feed. The site of action of ghrelin receptors is unclear, but may involve an increase in expression of CART peptide in VAN in HF-fed CCK₁R⁻/⁻ mice.

  3. Gabapentin and the neurokinin(1) receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain.

    Science.gov (United States)

    Field, Mark J; Gonzalez, M Isabel; Tallarida, Ronald J; Singh, Lakhbir

    2002-11-01

    The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.

  4. A selective adenosine A2A receptor antagonist ameliorated hyperlocomotion in an animal model of lateral fluid percussion brain injury.

    Science.gov (United States)

    Mullah, Saad Habib-E-Rasul; Inaji, Motoki; Nariai, Tadashi; Ishibashi, Satoru; Ohno, Kikuo

    2013-01-01

    Increased concentration of extracellular adenosine after brain injury is supposed to be one of the causes of secondary brain damage. The purpose of the present study is to examine whether or not administration of adenosine A2A receptor antagonist may be efficacious in ameliorating neurological symptoms by blocking secondary brain damage through cascades initiated by adenosine A2a receptor.Mongolian gerbils were divided into four groups: the trauma-medication (T-M), trauma-saline (T-S), sham-medication (S-M), and sham-saline (S-S) groups. Trauma groups received lateral fluid percussion injury. Medication groups received i.p. injection of SCH58261 (selective adenosine A2A receptor antagonist) until the fifth post-injury day. Open-field locomotion test and grabbing test were conducted before and 1, 3, 5, 7, and 9 days after injury.The total distance of movement in the T-S group was significantly greater than in the other three groups at all time points. In the T-M group, administration of SCH58261 significantly blocked hyperlocomotion, which was observed in the T-S group. There was no significant difference in the total distance among the T-M, S-M, and S-S groups. In the grabbing test, grabbing time was significantly increased in the T-S group 3, 5, 7, and 9 days after the operation. SCH58261 also improved grabbing time in the T-M group.Adenosine A2A antagonist successfully suppressed the trauma-induced hyperlocomotion, presumably by blocking secondary brain damage.

  5. [Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists].

    Science.gov (United States)

    Guo, Yan-shen; Guo, Zong-ru

    2009-03-01

    Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

  6. Striatal pre- and postsynaptic profile of adenosine A(2A receptor antagonists.

    Directory of Open Access Journals (Sweden)

    Marco Orru

    Full Text Available Striatal adenosine A(2A receptors (A(2ARs are highly expressed in medium spiny neurons (MSNs of the indirect efferent pathway, where they heteromerize with dopamine D(2 receptors (D(2Rs. A(2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1 receptors (A(1Rs. It has been hypothesized that postsynaptic A(2AR antagonists should be useful in Parkinson's disease, while presynaptic A(2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261 showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2AR-D(2R and A(1R-A(2AR heteromers to determine possible differences in the affinity of these compounds for different A(2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2AR when co-expressed with D(2R than with A(1R. KW-6002 showed the best relative affinity for A(2AR co-expressed with D(2R than co-expressed with A(1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile

  7. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    Science.gov (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  8. Haplotypes of the interleukin-1 receptor antagonist gene, interleukin-1 receptor antagonist mRNA levels and the risk of myocardial infarction

    NARCIS (Netherlands)

    van Minkelen, Rick; Wettinger, Stephanie Bezzina; de Visser, Marieke C.H.; Vos, Hans L.; Reitsma, Pieter H.; Rosendaal, Frits R.; Bertina, Rogier M.; Doggen, Catharina Jacoba Maria

    2009-01-01

    Background The overall effect of the major pro-inflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. We recently found that haplotype 5 (H5) of the gene (IL1RN) coding for the interleukin-1 receptor antagonist (IL-1Ra), the natural inhibitor of IL-1, is

  9. Molecular basis for antagonistic activity of anifrolumab, an anti-interferon-α receptor 1 antibody.

    Science.gov (United States)

    Peng, Li; Oganesyan, Vaheh; Wu, Herren; Dall'Acqua, William F; Damschroder, Melissa M

    2015-01-01

    Anifrolumab (anifrolumab) is an antagonist human monoclonal antibody that targets interferon α receptor 1 (IFNAR1). Anifrolumab has been developed to treat autoimmune diseases and is currently in clinical trials. To decipher the molecular basis of its mechanism of action, we engaged in multiple epitope mapping approaches to determine how it interacts with IFNAR1 and antagonizes the receptor. We identified the epitope of anifrolumab using enzymatic fragmentation, phage-peptide library panning and mutagenesis approaches. Our studies revealed that anifrolumab recognizes the SD3 subdomain of IFNAR1 with the critical residue R(279). Further, we solved the crystal structure of anifrolumab Fab to a resolution of 2.3 Å. Guided by our epitope mapping studies, we then used in silico protein docking of the anifrolumab Fab crystal structure to IFNAR1 and characterized the corresponding mode of binding. We find that anifrolumab sterically inhibits the binding of IFN ligands to IFNAR1, thus blocking the formation of the ternary IFN/IFNAR1/IFNAR2 signaling complex. This report provides the molecular basis for the mechanism of action of anifrolumab and may provide insights toward designing antibody therapies against IFNAR1.

  10. A new pyrrolyl-quinoxalinedione series of non-NMDA glutamate receptor antagonists: pharmacological characterization and comparison with NBQX and valproate in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W; Lehmann, H; Behl, B; Seemann, D; Teschendorf, H J; Hofmann, H P; Lubisch, W; Höger, T; Lemaire, H G; Gross, G

    1999-01-01

    Antagonists at the ionotropic non-NMDA [AMPA (amino-methyl proprionic acid)/kainate] type of glutamate receptors have been suggested to possess several advantages compared to NMDA (N-methyl-D-aspartate) receptor antagonists, particularly in terms of risk/benefit ratio, but the non-NMDA receptor antagonists available so far have not fulfilled this promise. From a large series of pyrrolyl-quinoxalinedione derivatives, we selected six new competitive non-NMDA receptor antagonists. The basis of selection was high potency and selectivity for AMPA and/or kainate receptors, high in vivo potency after systemic administration, and an acceptable ratio between neuroprotective or anticonvulsant effects and adverse effects. Pharmacological characteristics of these novel compounds are described in this study with special emphasis on their effects in the kindling model of temporal lobe epilepsy, the most common type of epilepsy in humans. In most experiments, NBQX and the major antiepileptic drug valproate were used for comparison with the novel compounds. The novel non-NMDA receptor antagonists markedly differed in their AMPA and kainate receptor affinities from NBQX. Thus, while NBQX essentially did not bind to kainate receptors at relevant concentrations, several of the novel compounds exhibited affinity to rat brain kainate receptors or recombinant kainate receptor subtypes in addition to AMPA receptors. One compound, LU 97175, bound to native high affinity kainate receptors and rat GluR5-GluR7 subunits, i.e. low affinity kainate binding sites, with much higher affinities than to AMPA receptors. All compounds potently blocked AMPA-induced cell death in vitro and, except LU 97175, AMPA-induced convulsions in vivo. In the kindling model, compounds with a high affinity for GluR7 (LU 97175) or compounds (LU 115455, LU 136541) which potently bind to AMPA receptors and low affinity kainate receptor subunits were potent anticonvulsants in the kindling model, whereas the AMPA

  11. Effects of TRA-418, a novel TP-receptor antagonist, and IP-receptor agonist, on human platelet activation and aggregation.

    Science.gov (United States)

    Miyamoto, Mitsuko; Yamada, Naohiro; Ikezawa, Shiho; Ohno, Michihiro; Otake, Atsushi; Umemura, Kazuo; Matsushita, Teruo

    2003-11-01

    [4-[2-(1,1-Diphenylethylsulfanyl)-ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxy]-acetic acid N-Methyl-d-glucamine salt (TRA-418) has both thromboxane A2 (TP)-receptor antagonist and prostacyclin (IP)-receptor agonist properties. The present study examined the advantageous effects of TRA-418 based on the dual activities, over an agent having either activity alone and also the difference in the effects of TRA-418 and a glycoprotein alphaIIb/beta3 integrin (GPIIb/IIIa) inhibitor. TRA-418 inhibited platelet GPIIb/IIIa activation as well as P-selectin expression induced by adenosine 5'-diphosphate, thrombin receptor agonist peptide 1-6 (Ser-Phe-Leu-Leu-Arg-Asn-NH2), and U-46619 in the presence of epinephrine (U-46619+ epinephrine). TRA-418 also inhibited platelet aggregation induced by those platelet-stimulants in Ca2+ chelating anticoagulant, citrate and in nonchelating anticoagulant, d-phenylalanyl-l-prolyl-l-arginyl-chloromethyl ketone (PPACK). The TP-receptor antagonist SQ-29548 inhibited only U-46619+epinephrine-induced GPIIb/IIIa activation, P-selectin expression, and platelet aggregation. The IP-receptor agonist beraprost sodium inhibited platelet activation. Beraprost also inhibited platelet aggregation induced by platelet stimulants we tested in citrate and in PPACK. The GPIIb/IIIa inhibitor abciximab blocked GPIIb/IIIa activation and platelet aggregation. However, abciximab showed slight inhibitory effects on P-selectin expression. TRA-418 is more advantageous as an antiplatelet agent than TP-receptor antagonists or IP-receptor agonists separately used. TRA-418 showed a different inhibitory profile from abciximab in the effects on P-selectin expression.

  12. Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats.

    Science.gov (United States)

    Fang, Qin; Li, Fang-Qiong; Li, Yan-Qin; Xue, Yan-Xue; He, Ying-Ying; Liu, Jian-Feng; Lu, Lin; Wang, Ji-Shi

    2011-10-01

    Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB(1) receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB(1) receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0mg/kg) and saline. Rimonabant at a dose of 3.0mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB(1) receptors play a role in nicotine reward memory, suggesting that CB(1) receptor antagonists may be a potential target for managing nicotine addiction.

  13. Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

    Science.gov (United States)

    Taylor, A M W; Roberts, K W; Pradhan, A A; Akbari, H A; Walwyn, W; Lutfy, K; Carroll, F I; Cahill, C M; Evans, C J

    2015-01-01

    The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the μ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The

  14. Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity.

    Science.gov (United States)

    Galici, Ruggero; Boggs, Jamin D; Miller, Kirsten L; Bonaventure, Pascal; Atack, John R

    2008-03-01

    5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30 mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10 mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.

  15. Dopamine D2 antagonist-induced striatal Nur77 expression requires activation of mGlu5 receptors by cortical afferents

    Directory of Open Access Journals (Sweden)

    Jérôme eMaheux

    2012-08-01

    Full Text Available Dopamine D2 receptor antagonists modulate gene transcription in the striatum. However, the molecular mechanism underlying this effect remains elusive. Here we used the expression of Nur77, a transcription factor of the orphan nuclear receptor family, as readout to explore the role of dopamine, glutamate and adenosine receptors in the effect of a dopamine D2 antagonist in the striatum. First, we investigated D2 antagonist-induced Nur77 mRNA in D2L receptor knockout mice. Surprisingly, deletion of the D2L receptor isoform did not reduce eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Next, we tested if an ibotenic acid-induced cortical lesion could block the effect of eticlopride on Nur77 expression. Cortical lesions strongly reduced eticlopride-induced striatal upregulation of Nur77 mRNA. Then, we investigated if glutamatergic neurotransmission could modulate eticlopride-induced Nur77 expression. A combination of a metabotropic glutamate type 5 (mGlu5 and adenosine A2A receptor antagonists abolished eticlopride-induced upregulation of Nur77 mRNA levels in the striatum. Direct modulation of Nur77 expression by striatal glutamate and adenosine receptors was confirmed using corticostriatal organotypic cultures. Taken together, these results indicate that blockade of postsynaptic D2 receptors is not sufficient to trigger striatal transcriptional activity and that interaction with corticostriatal presynaptic D2 receptors and subsequent activation of postsynaptic glutamate and adenosine receptors in the striatum is required. Thus, these results uncover an unappreciated role of presynaptic D2 heteroreceptors and support a prominent role of glutamate in the effect of D2 antagonists.

  16. Heterogeneity of binding of muscarinic receptor antagonists in rat brain homogenates

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J.H.; el-Fakahany, E.E.

    1985-06-01

    The binding properties of (-)-(/sup 3/H)quinuclidinyl benzilate and (/sup 3/H) N-methylscopolamine to muscarinic acetylcholine receptors have been investigated in rat brain homogenates. The binding of both antagonists demonstrated high affinity and saturability. Analysis of the binding data resulted in linear Scatchard plots. However, (-)-(/sup 3/H)quinuclidinyl benzilate showed a significantly higher maximal binding capacity than that of (/sup 3/H)N-methylscopolamine. Displacement of both ligands with several muscarinic receptor antagonists resulted in competition curves in accordance with the law of mass-action for quinuclidinyl benzilate, atropine and scopolamine. A similar profile was found for the quaternary ammonium analogs of atropine and scopolamine when (/sup 3/H)N-methylscopolamine was used to label the receptors. However, when these hydrophilic antagonists were used to displace (-)-(/sup 3/H) quinuclidinyl benzilate binding, they showed interaction with high- and low-affinity binding sites. On the other hand, the nonclassical muscarinic receptor antagonist, pirenzepine, was able to displace both ligands from two binding sites. The present data are discussed in terms of the relationship of this anomalous heterogenity of binding of these hydrophilic muscarinic receptor antagonists and the proposed M1 and M2 receptor subtypes.

  17. Evidence that the angiotensin at 2-receptor agonist compound 21 is also a low affinity thromboxane TXA2-receptor antagonist

    DEFF Research Database (Denmark)

    Fredgart, M.; Leurgans, T.; Stenelo, M.;

    2015-01-01

    Objective: The objective of this study was to test whether Compound 21 (C21), a high-affinity, non-peptide angiotensinAT2-receptor agonist, is also an antagonist of thromboxane A2 (TXA2) receptors thus reducing both vasoconstriction and platelet aggregation. Design and method: Binding of C21 to t...

  18. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral cir...

  19. Montelukast, a leukotriene receptor antagonist, modulates lung CysLT1

    Institute of Scientific and Technical Information of China (English)

    ZHANGYan-Jun; ZHANGLei; WANGShao-Bin; SHENHua-Hao; WEIEr-Qing

    2004-01-01

    AIM: To determine the expressions of cysteinyl leukotriene receptors, CysLT, and CysLT2 , in airway eosinophilic inflammation of OVA-induced asthmatic mice and the modulation by montelukast, a CysLT1 receptor antagonist. METHODS: Asthma model was induced by chronic exposure to ovalbumin (OVA) in C57BL/6 mice. The eosinophils in

  20. Pyrrolidin-3-yl-N-methylbenzamides as potent histamine 3 receptor antagonists.

    Science.gov (United States)

    Zhou, Dahui; Gross, Jonathan L; Sze, Jean Y; Adedoyin, Adedayo B; Bowlby, Mark; Di, Li; Platt, Brian J; Zhang, Guoming; Brandon, Nicholas; Comery, Thomas A; Robichaud, Albert J

    2011-10-01

    On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.

  1. Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity.

    Science.gov (United States)

    de Lera Ruiz, Manuel; Zheng, Junying; Berlin, Michael Y; McCormick, Kevin D; Aslanian, Robert G; West, Robert; Hwa, Joyce; Lachowicz, Jean; van Heek, Margaret

    2013-11-01

    A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.

  2. No effect of angiotensin II AT(2)-receptor antagonist PD 123319 on cerebral blood flow autoregulation

    DEFF Research Database (Denmark)

    Estrup, T M; Paulson, O B; Strandgaard, S

    2001-01-01

    Blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin AT1-receptor antagonists shift the limits of autoregulation of cerebral blood flow (CBF) towards lower blood pressure (BP). The role of AT2-receptors in the regulation of the cerebral...

  3. Computer-aided molecular modeling of a thromboxane receptor antagonist S-145 and its related compounds.

    Science.gov (United States)

    Ezumi, K; Yamakawa, M; Narisada, M

    1990-04-01

    Conformational analyses on thromboxane A2 (TxA2), its receptor agonist, U-46619, and its receptor antagonist, sulotroban, were carried out by molecular mechanics (MMFF) or molecular orbital (MNDO) methods. Two kinds of putative active conformations of TxA2 and the agonist were proposed on the basis of these results by referring to the hairpin conformation hypothesis. From the superposition of stable conformers of sulotroban on those conformers, the molecular structural requirements for potent TxA2 receptor antagonism were elucidated. S-145 in which these requirements are satisfied was a very potent TxA2 antagonist.

  4. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan

    2011-01-01

     pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors......, calindol and NPS 2143, which both display ~30-fold selectivity for the calcium-sensing receptor compared to GPRC6A. The antagonists constitute novel research tools toward investigating the signaling mechanism of the GPRC6A receptor at the cellular level and serve as initial ligands for further optimization...

  5. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe2435.39 is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na+ allosteric site in contrast to PAR2 agonist that showed Na+ relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  6. Pharmacophore-based virtual screening, biological evaluation and binding mode analysis of a novel protease-activated receptor 2 antagonist.

    Science.gov (United States)

    Cho, Nam-Chul; Seo, Seoung-Hwan; Kim, Dohee; Shin, Ji-Sun; Ju, Jeongmin; Seong, Jihye; Seo, Seon Hee; Lee, Iiyoun; Lee, Kyung-Tae; Kim, Yun Kyung; No, Kyoung Tai; Pae, Ae Nim

    2016-08-01

    Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor, mediating inflammation and pain signaling in neurons, thus it is considered to be a potential therapeutic target for inflammatory diseases. In this study, we performed a ligand-based virtual screening of 1.6 million compounds by employing a common-feature pharmacophore model and two-dimensional similarity search to identify a new PAR2 antagonist. The common-feature pharmacophore model was established based on the biological screening results of our in-house library. The initial virtual screening yielded a total number of 47 hits, and additional biological activity tests including PAR2 antagonism and anti-inflammatory effects resulted in a promising candidate, compound 43, which demonstrated an IC50 value of 8.22 µM against PAR2. In next step, a PAR2 homology model was constructed using the crystal structure of the PAR1 as a template to explore the binding mode of the identified ligands. A molecular docking method was optimized by comparing the binding modes of a known PAR2 agonist GB110 and antagonist GB83, and applied to predict the binding mode of our hit compound 43. In-depth docking analyses revealed that the hydrophobic interaction with Phe243(5.39) is crucial for PAR2 ligands to exert antagonistic activity. MD simulation results supported the predicted docking poses that PAR2 antagonist blocked a conformational rearrangement of Na(+) allosteric site in contrast to PAR2 agonist that showed Na(+) relocation upon GPCR activation. In conclusion, we identified new a PAR2 antagonist together with its binding mode, which provides useful insights for the design and development of PAR2 ligands.

  7. Synthesis and Biological Evaluation of Substituted Desloratadines as Potent Arginine Vasopressin V2 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Shuai Mu

    2014-02-01

    Full Text Available Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by 1H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

  8. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.

    Science.gov (United States)

    della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G

    1996-01-01

    The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work.

  9. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia – critical appraisal of suvorexant

    Science.gov (United States)

    Norman, Jessica L; Anderson, Sarah L

    2016-01-01

    Insomnia, a highly prevalent disorder, can be detrimental to patients’ overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia. PMID:27471419

  10. THE INTERACTION OF SELECTIVE AND NONSELECTIVE ANTAGONISTS WITH PREJUNCTIONAL AND POSTJUNCTIONAL MUSCARINIC RECEPTOR SUBTYPES IN THE GUINEA-PIG TRACHEA

    NARCIS (Netherlands)

    TENBERGE, REJ; ROFFEL, AF; ZAAGSMA, J

    1993-01-01

    Muscarinic receptor antagonists were used to study prejunctional M2 and postjunctional M3 receptors in the isolated guinea pig trachea. The effects of four M2-selective muscarinic receptor antagonists (gallamine, methoctramine, AQ-RA 741 and AF-DX 116) were studied on twitch contractions, elicited

  11. THE INTERACTION OF SELECTIVE AND NONSELECTIVE ANTAGONISTS WITH PREJUNCTIONAL AND POSTJUNCTIONAL MUSCARINIC RECEPTOR SUBTYPES IN THE GUINEA-PIG TRACHEA

    NARCIS (Netherlands)

    TENBERGE, REJ; ROFFEL, AF; ZAAGSMA, J

    1993-01-01

    Muscarinic receptor antagonists were used to study prejunctional M2 and postjunctional M3 receptors in the isolated guinea pig trachea. The effects of four M2-selective muscarinic receptor antagonists (gallamine, methoctramine, AQ-RA 741 and AF-DX 116) were studied on twitch contractions, elicited b

  12. Blockade of catecholamine-induced growth by adrenergic and dopaminergic receptor antagonists in Escherichia coli O157:H7, Salmonella enterica and Yersinia enterocolitica

    Directory of Open Access Journals (Sweden)

    Lyte Mark

    2007-01-01

    Full Text Available Abstract Background The ability of catecholamines to stimulate bacterial growth was first demonstrated just over a decade ago. Little is still known however, concerning the nature of the putative bacterial adrenergic and/or dopaminergic receptor(s to which catecholamines (norepinephrine, epinephrine and dopamine may bind and exert their effects, or even whether the binding properties of such a receptor are similar between different species. Results Use of specific catecholamine receptor antagonists revealed that only α, and not β, adrenergic antagonists were capable of blocking norepinephrine and epinephrine-induced growth, while antagonism of dopamine-mediated growth was achieved with the use of a dopaminergic antagonist. Both adrenergic and dopaminergic antagonists were highly specific in their mechanism of action, which did not involve blockade of catecholamine-facilitated iron-acquisition. Use of radiolabeled norepinephrine suggested that the adrenergic antagonists could be acting by inhibiting catecholamine uptake. Conclusion The present data demonstrates that the ability of a specific pathogen to respond to a particular hormone is dependent upon the host anatomical region in which the pathogen causes disease as well as the neuroanatomical specificity to which production of the particular hormone is restricted; and that both are anatomically coincidental to each other. As such, the present report suggests that pathogens with a high degree of exclusivity to the gastrointestinal tract have evolved response systems to neuroendocrine hormones such as norepinephrine and dopamine, but not epinephrine, which are found with the enteric nervous system.

  13. Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human breast cancer cell lines.

    Science.gov (United States)

    Tanaka, Satoshi; Sakaguchi, Minoru; Yoneyama, Hiroki; Usami, Yoshihide; Harusawa, Shinya

    2016-11-18

    Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H3 receptor (H3R) plays a role in the proliferation of breast cancer cells. We recently developed the non-imidazole H3R antagonist OUP-186 which exhibited a potent and selective human H3R antagonistic activity as well as no activity against the human histamine H4 receptor (H4R). In this study, we compared the effects of OUP-186 on the proliferation of estrogen receptor negative (ER-) breast cancer cells (MDA-MB-231) and ER+ breast cancer cells (MCF7) to the effects of clobenpropit (potent imidazole-containing H3R antagonist). OUP-186 and clobenpropit suppressed the proliferation of breast cancer cells. The IC50 values at 48 h for OUP-186 and clobenpropit were approximately 10 μM and 50 μM, respectively. Furthermore, OUP-186 potently induced cell death by activating caspase-3/7, whereas cell death was only slightly induced by clobenpropit. In addition, OUP-186 treatment blocked the proliferation increase triggered by 100 μM (R)-(-)-α-methylhistamine (H3R agonist). The use of 4-methylhistamine (H4R agonist) and JNJ10191584 (selective H4R antagonist) did not affect breast cancer proliferation. These results indicate that OUP-186 potently suppresses proliferation and induces caspase-dependent apoptotic death in both ER+ and ER-breast cancer cells.

  14. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

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    Wiebke Janssen

    2015-01-01

    Full Text Available Objective. The serotonin (5-HT pathway was shown to play a role in pulmonary hypertension (PH, but its functions in right ventricular failure (RVF remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist or SB204741 (5-HT2B receptor antagonist on right heart function and structure upon pulmonary artery banding (PAB in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid or SB204741 (5 mg/kg day. Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI, and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  15. 5-HT2B receptor antagonists inhibit fibrosis and protect from RV heart failure.

    Science.gov (United States)

    Janssen, Wiebke; Schymura, Yves; Novoyatleva, Tatyana; Kojonazarov, Baktybek; Boehm, Mario; Wietelmann, Astrid; Luitel, Himal; Murmann, Kirsten; Krompiec, Damian Richard; Tretyn, Aleksandra; Pullamsetti, Soni Savai; Weissmann, Norbert; Seeger, Werner; Ghofrani, Hossein Ardeschir; Schermuly, Ralph Theo

    2015-01-01

    The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid) or SB204741 (5 mg/kg day). Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  16. Effects of H1–receptor antagonists in antidepressant tests in rats

    OpenAIRE

    Chitra C. Khanwelkar

    2008-01-01

    : Considering the vast data suggesting the role of brain histamine(HA) in behaviour,emotions,anxiety and depression;four H1-receptor antagonists; promethazine, diphenhydramine, cyclizine and pheniramine were subjected to antidepressant tests in rats. All H1 – antagonists behaved like antidepressants in animal tests. They antagonized reserpine induced catalepsy, potentiated methamphetamine induced stereotypy and reduced the period of immobility in Porsolt’s behavioural despair test. It is sug...

  17. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach

    Directory of Open Access Journals (Sweden)

    Miguel Muñoz

    2016-01-01

    Full Text Available Gastrointestinal (GI cancer is the term for a group of cancers affecting the digestive system. After binding to the neurokinin-1 (NK-1 receptor, the undecapeptide substance P (SP regulates GI cancer cell proliferation and migration for invasion and metastasis, and controls endothelial cell proliferation for angiogenesis. SP also exerts an antiapoptotic effect. Both SP and the NK-1 receptor are located in GI tumor cells, the NK-1 receptor being overexpressed. By contrast, after binding to the NK-1 receptor, NK-1 receptor antagonists elicit the inhibition (epidermal growth factor receptor inhibition of the proliferation of GI cancer cells in a concentration-dependent manner, induce the death of GI cancer cells by apoptosis, counteract the Warburg effect, inhibit cancer cell migration (counteracting invasion and metastasis, and inhibit angiogenesis (vascular endothelial growth factor inhibition. NK-1 receptor antagonists are safe and well tolerated. Thus, the NK-1 receptor could be considered as a new target in GI cancer and NK-1 receptor antagonists (eg, aprepitant could be a new promising approach for the treatment of GI cancer.

  18. Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix.

    Science.gov (United States)

    Barkin, Jack; Burton, Shelley; Lambert, Carole

    2016-02-01

    The gonadotropin-releasing hormone (GnRH) receptor antagonist degarelix has several unique characteristics compared to luteinizing hormone-releasing hormone (LHRH) analogs used in the management of prostate cancer. Notable differences of GnRH receptor antagonists include no flare reaction, and a more rapid suppression of testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prostate-specific antigen (PSA) compared to LHRH analogs. Despite emerging evidence supporting the use of GnRH receptor antagonists over the more widely used LHRH analogs in the management of prostate cancer, physicians may be reluctant to prescribe degarelix. They may be concerned about patient complaints about injection-site reactions (ISRs). The subcutaneous injection of degarelix has been associated with a higher rate of ISRs compared with the intramuscular injections of LHRH analogs. This "How I Do It" article describes techniques and strategies that have been developed by physicians and nurses to reduce the discomfort associated with the subcutaneous delivery of degarelix.

  19. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

    Science.gov (United States)

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2014-06-01

    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

  20. Orexin 1 receptor antagonists in compulsive behaviour and anxiety: possible therapeutic use.

    Directory of Open Access Journals (Sweden)

    Emilio eMerlo-Pich

    2014-02-01

    Full Text Available Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were early on associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders, in this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1 antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioural and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

  1. Kinetic properties of 'dual' orexin receptor antagonists at OX1R and OX2R orexin receptors.

    Directory of Open Access Journals (Sweden)

    Gabrielle Elizabeth Callander

    2013-12-01

    Full Text Available Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various ‘dual’ orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [3H]-BBAC ((S-N-([1,1'-biphenyl]-2-yl-1-(2-((1-methyl-1H-benzo[d]imidazol-2-ylthioacetylpyrrolidine-2-carboxamide. In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-ylmethyl-9-(4-methoxypyrimidin-2-yl-2,9-diazaspiro[5.5]undecan-1-one bind rapidly and reach equilibrium very quickly in both binding and / or functional assays. Overall, the dual antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the dual antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.

  2. Characterization of PCS1055, a novel muscarinic M4 receptor antagonist.

    Science.gov (United States)

    Croy, Carrie H; Chan, Wai Y; Castetter, Andrea M; Watt, Marla L; Quets, Anne T; Felder, Christian C

    2016-07-05

    Identification of synthetic ligands selective for muscarinic receptor subtypes has been challenging due to the high sequence identity and structural homology among the five muscarinic acetylcholine receptors. Here, we report the pharmacological characterization of PCS1055, a novel muscarinic M4 receptor antagonist. PCS1055 inhibited radioligand [(3)H]-NMS binding to the M4 receptor with a Ki=6.5nM. Though the potency of PCS1055 is lower than that of pan-muscarinic antagonist atropine, it has better subtype selectivity over previously reported M4-selective reagents such as the muscarinic-peptide toxins (Karlsson et al., 1994; Santiago and Potter, 2001a) at the M1 subtype, and benzoxazine ligand PD102807 at the M3-subtype (Bohme et al., 2002). A detailed head-to-head comparison study using [(3)H]-NMS competitive binding assays characterizes the selectivity profiles of PCS1055 to that of other potent muscarinic-antagonist compounds PD102807, tropicamide, AF-DX-384, pirenzapine, and atropine. In addition to binding studies, the subtype specificity of PCS1055 is also demonstrated by functional receptor activation as readout by GTP-γ-[(35)S] binding. These GTP-γ-[(35)S] binding studies showed that PCS1055 exhibited 255-, 69.1-, 342- and >1000-fold greater inhibition of Oxo-M activity at the M4 versus the M1-, M2(-), M3-or M5 receptor subtypes, respectively. Schild analyses indicates that PCS1055 acts as a competitive antagonist to muscarinic M4 receptor, and confirms the affinity of the ligand to be low nanomolar, Kb=5.72nM. Therefore, PCS1055 represents a new M4-preferring antagonist that may be useful in elucidating the roles of M4 receptor signaling.

  3. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting.

    Science.gov (United States)

    Hargreaves, Richard; Ferreira, Juan Camilo Arjona; Hughes, David; Brands, Jos; Hale, Jeff; Mattson, Britta; Mills, Sandy

    2011-03-01

    Chemotherapy can be a life-prolonging treatment for many cancer patients, but it is often associated with profound nausea and vomiting that is so distressing that patients may delay or decline treatment to avoid these side effects. EMEND (aprepitant) is the first and only neurokinin-1 (NK-1) receptor antagonist available on the market for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Aprepitant acts centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy. By controlling nausea and vomiting, EMEND helps improve patients' daily living and their ability to complete multiple cycles of chemotherapy. The development of aprepitant included a novel nanoparticle formulation to optimize oral absorption and innovative chemistry to discover a prodrug form suitable for intravenous administration to improve compliance and convenience for healthcare professionals and cancer patients.

  4. Effects of the NMDA receptor antagonists on deltamethrin-induced striatal dopamine release in conscious unrestrained rats.

    Science.gov (United States)

    Morikawa, Takuya; Furuhama, Kazuhisa

    2009-08-01

    To better understand the neurotoxicity caused by the pyrethroid pesticide, we examined the effects of the N-methyl-D-aspartate (NMDA) receptor antagonists MK-801, a non-competitive cation channel blocker, and 2-amino-5-phosphonovaleric acid (APV), a competitive Na(+) channel blocker, on extracellular dopamine levels in male Sprague-Dawley rats receiving the type II pyrethroid deltamethrin using an in vivo microdialysis system. Deltamethrin (60 mg/kg, i.p.) evidently increased striatal dopamine levels with a peak time of 120 min, and the local infusion (i.c.) of either MK-801(650 muM) or APV (500 muM) completely blocked these actions. The fluctuation in the dopamine metabolite 3-MT also resembled that in dopamine. Our results suggest that dopamine-releasing neurons would be modulated via the NMDA receptor by the excitatory glutamatergic neurons after deltamethrin treatment.

  5. Tranylcypromine substituted cis-hydroxycyclobutylnaphthamides as potent and selective dopamine D₃ receptor antagonists.

    Science.gov (United States)

    Chen, Jianyong; Levant, Beth; Jiang, Cheng; Keck, Thomas M; Newman, Amy Hauck; Wang, Shaomeng

    2014-06-12

    We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (K(i) = 12.8 μM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K(i) values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a β-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor.

  6. Recombinant interleukin-1 receptor antagonist attenuates the severity of chronic pancreatitis induced by TNBS in rats.

    Science.gov (United States)

    Xu, Chunfang; Shen, Jiaqing; Zhang, Jing; Jia, Zhenyu; He, Zhilong; Zhuang, Xiaohui; Xu, Ting; Shi, Yuqi; Zhu, Shunying; Wu, Mingyuan; Han, Wei

    2015-02-15

    Chronic pancreatitis (CP) is a common disease in the department of gastroenterology, with the main symptoms of exocrine and/or endocrine insufficiency and abdominal pain. The pathogenic mechanism of CP is still not fully clarified and the aims of treatment now are to relieve symptoms. In this study, we attempted to find a connection between interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1Ra) in trinitrobenzene sulfonic acid (TNBS)-induced chronic pancreatitis, and then the therapeutic effect of recombinant IL-1Ra was also detected in the CP model. Chronic pancreatitis was induced by intraductal infusion of TNBS in SD rats followed by a consecutive administration of rIL-1Ra, and the histological changes and collagen content in the pancreas were measured, as well as the abdominal hypersensitivity. We found that rhIL-1Ra could attenuate the severity of chronic pancreatic injury, modulate the extracellular matrix secretion, focal proliferation and apoptosis, and cellular immunity in TNBS-induced CP. Interestingly, rIL-1Ra could also block the pancreatitis-induced referred abdominal hypersensitivity. In conclusion, IL-1Ra may play a protective role in CP and rIL-1Ra would be a potential therapeutic target for the treatment of CP, while its possible mechanisms and clinical usage still need further investigation.

  7. The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia

    Science.gov (United States)

    Sauter, Nadine S.; Schulthess, Fabienne T.; Galasso, Ryan; Castellani, Lawrence W.; Maedler, Kathrin

    2008-01-01

    Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the β-cell. IL-1Ra protected islets from HFD treated animals from β-cell apoptosis, induced β-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves β-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes. PMID:18239070

  8. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain.

    Science.gov (United States)

    DeKosky, S T; Styren, S D; O'Malley, M E; Goss, J R; Kochanek, P; Marion, D; Evans, C H; Robbins, P D

    1996-01-01

    Traumatic brain injury (TBI) induces astrocytic and microglial activation and proliferation and augmented production of the cytokine interleukin-1 beta (IL-1 beta) and nerve growth factor (NGF). The increase in NGF temporally follows the increase in IL-1 beta, suggesting that the IL-1 beta up-regulation after trauma directly induces the increase in NGF. We examined the effect of IL-1 receptor antagonist protein (IL-1ra) on microglial proliferation and NGF production in rat cortex, following two different models of TBI. Rabbit fibroblasts infected with a retroviral vector containing the human IL-1ra gene were implanted into the wound cavity immediately following a cortical stab wound or 6 hours after a weight drop-induced trauma. Both microglial proliferation and NGF up-regulation were decreased significantly in animals receiving IL-1ra-expressing cells compared with animals receiving naive (untransfected) fibroblasts. These data demonstrate that the increase in NGF after central nervous system trauma is directly mediated through IL-1 beta and that blocking IL-1 beta following brain injury leads to suppression of an NGF-mediated reparative response. Such blockade of inflammation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.

  9. Optimization of ketone-based P2Y(12) receptor antagonists as antithrombotic agents: pharmacodynamics and receptor kinetics considerations.

    Science.gov (United States)

    Giordanetto, Fabrizio; Bach, Peter; Zetterberg, Fredrik; Antonsson, Thomas; Bylund, Ruth; Johansson, Johan; Sellén, Mikael; Brown, David; Hideståhl, Lotta; Berntsson, Pia; Hovdal, Daniel; Zachrisson, Helen; Björkman, Jan-Arne; van Giezen, J J J

    2014-07-01

    Modification of a series of P2Y12 receptor antagonists by replacement of the ester functionality was aimed at minimizing the risk of in vivo metabolic instability and pharmacokinetic variability. The resulting ketones were then optimized for their P2Y12 antagonistic and anticoagulation effects in combination with their physicochemical and absorption profiles. The most promising compound showed very potent antiplatelet action in vivo. However, pharmacodynamic-pharmacokinetic analysis did not reveal a significant separation between its anti-platelet and bleeding effects. The relevance of receptor binding kinetics to the in vivo profile is described. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Benzodiazepine receptor antagonists for acute and chronic hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Kjaergard, L L; Gluud, C

    2001-01-01

    The pathogenesis of hepatic encephalopathy is unknown. It has been suggested that liver failure leads to the accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition which may progress to coma. Several trials have assessed benzodiazepine receptor...

  11. Combinatorial assembly of small molecules into bivalent antagonists of TrkC or TrkA receptors.

    Directory of Open Access Journals (Sweden)

    Fouad Brahimi

    Full Text Available A library of peptidomimetics was assembled combinatorially into dimers on a triazine-based core. The pharmacophore corresponds to β-turns of the neurotrophin polypeptides neurotrophin-3 (NT-3, nerve growth factor (NGF, or brain-derived neurotrophic factor (BDNF. These are the natural ligands for TrkC, TrkA, and TrkB receptors, respectively. The linker length and the side-chain orientation of each monomer within the bivalent mimics were systematically altered, and the impact of these changes on the function of each ligand was evaluated. While the monovalent peptidomimetics had no detectable binding or bioactivity, four bivalent peptidomimetics (2c, 2d, 2e, 3f are selective TrkC ligands with antagonistic activity, and two bivalent peptidomimetics (1a, 1b are TrkC and TrkA ligands with antagonistic activity. All these bivalent compounds block ligand-dependent receptor activation and cell survival, without affecting neuritogenic differentiation. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb specific biological signals, and may be used as pharmacological probes or as therapeutic leads. The concept of altering side-chain, linker length, and sequence orientation of a subunit within a pharmacophore provides an easy modular approach to generate larger libraries with diversified bioactivity.

  12. Influence of leptin and GABAB-receptor agonist and antagonist on neurons of the hypothalamic infundibular nucleus in the chicken.

    Science.gov (United States)

    Bogatyrev, S; Yakimova, K S; Tzschentke, B

    2017-04-01

    In birds and mammals, the neuroendocrine regulation of energy balance is conserved in many aspects. Despite significant similarities between the two groups, differences in the regulatory mechanisms were detected. The present study was performed to carry out investigations of the influence of human leptin and GABAB-receptor agonist and antagonist on the firing rate of neurons of the Nucleus infundibuli hypothalami in brain slices from juvenile chickens. For the first time, we demonstrated a clear, dose-related change in the firing rate of hypothalamic neurons in juvenile chickens after the acute application of recombinant human leptin (1, 10, and 100 nM). All investigated neurons increased their subsequent firing rate. Application of GABAB-receptor agonist baclofen (1 µM) blocked, while antagonist CGP 35348 (10 µM) increased the spontaneous neuronal activity. Simultaneous application of baclofen and leptin reduced the effect observed from single leptin application. This was not found after simultaneously application of leptin and CGP. Altogether, our results indicate that in bird brain slices, and exemplarily in those of the chicken, hypothalamic neurons show mammalian-like responsiveness after acute leptin and GABA application. GABAB-mechanisms involved in GABA release play a likely important role in the leptin-mediated effects on NI neurons via functional leptin receptors.

  13. Antagonists of the human A(2A) receptor. Part 6: Further optimization of pyrimidine-4-carboxamides.

    Science.gov (United States)

    Gillespie, Roger J; Bamford, Samantha J; Clay, Alex; Gaur, Suneel; Haymes, Tim; Jackson, Philip S; Jordan, Allan M; Klenke, Burkhard; Leonardi, Stefania; Liu, Jeanette; Mansell, Howard L; Ng, Sean; Saadi, Mona; Simmonite, Heather; Stratton, Gemma C; Todd, Richard S; Williamson, Douglas S; Yule, Ian A

    2009-09-15

    Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.

  14. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    OpenAIRE

    Wiebke Janssen; Yves Schymura; Tatyana Novoyatleva; Baktybek Kojonazarov; Mario Boehm; Astrid Wietelmann; Himal Luitel; Kirsten Murmann; Damian Richard Krompiec; Aleksandra Tretyn; Soni Savai Pullamsetti; Norbert Weissmann; Werner Seeger; Hossein Ardeschir Ghofrani; Ralph Theo Schermuly

    2015-01-01

    Objective. The serotonin (5-HT) pathway was shown to play a role in pulmonary hypertension (PH), but its functions in right ventricular failure (RVF) remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist) or SB204741 (5-HT2B receptor antagonist) on right heart function and structure upon pulmonary artery banding (PAB) in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg b...

  15. Metabotropic glutamate 2/3 receptor antagonists improve behavioral and prefrontal dopaminergic alterations in the chronic corticosterone-induced depression model in mice.

    Science.gov (United States)

    Ago, Yukio; Yano, Koji; Araki, Ryota; Hiramatsu, Naoki; Kita, Yuki; Kawasaki, Toshiyuki; Onoe, Hirotaka; Chaki, Shigeyuki; Nakazato, Atsuro; Hashimoto, Hitoshi; Baba, Akemichi; Takuma, Kazuhiro; Matsuda, Toshio

    2013-02-01

    Metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists have an antidepressant-like effect, but the exact mechanism still remains unclear. This study examined the effects of mGlu2/3 receptor antagonists in chronic corticosterone-treated mice which could be used as an animal model of depression. In the forced swim test, the mGlu2/3 receptor antagonists MGS0039 (1.0 mg/kg, i.p.) and LY341495 (0.3 mg/kg, i.p) significantly reduced the increased immobility time of mice pretreated with corticosterone (20 mg/kg, s.c.) for 21 days, while desipramine (30 mg/kg, i.p.) and fluoxetine (30 mg/kg, i.p.) did not. The antidepressant-like effect of LY341495 was not blocked by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist NBQX (10 mg/kg, i.p.). Systemic administration of LY341495 did not affect basal release of glutamate, dopamine or serotonin in the prefrontal cortex of the control or chronic corticosterone-treated mice. Chronic corticosterone markedly enhanced high K(+)-induced release of dopamine, but not serotonin or glutamate, in the prefrontal cortex. This neurochemical change was blocked by systemic administration of MGS0039 and LY341495, but not desipramine or fluoxetine. These results suggest that chronic corticosterone-treated mice could be used as an animal model of treatment-resistant depression. This study also suggests that the prefrontal dopaminergic system is involved in the antidepressant-like effect of mGlu2/3 receptor antagonists in the chronic corticosterone-induced depression model.

  16. SB-258741: a 5-HT7 receptor antagonist of potential clinical interest.

    Science.gov (United States)

    Pouzet, Bruno

    2002-01-01

    Recently, a series of 5-HT7 receptor antagonists have been developed (24,29,36,68). Among them SB-258741, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine, (compound "13" in 36,37) was one of the most potent and specific compounds. Due to a lack of specific ligands the pharmacology of 5-HT7 receptor antagonists is still relatively unexplored. It has been suggested, however, that 5-HT7 receptor ligands could be useful in the therapy of various disorders such as sleep disorders, schizophrenia, depression, migraine, epilepsy, pain, or memory impairment. Many of these conceivable indications are not supported by pharmacological data. It is, therefore, of particular interest to review the data generated from studies of one of these most potent and specific 5-HT7 receptor antagonists, SB-258741, with a goal of testing the validity of the proposed clinical indications. In this review, the author describes pharmacology of this compound in order to define its potential clinical use. The available safety pharmacology data are discussed in an attempt to predict potential side effects of specific 5-HT7 receptor antagonists.

  17. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    Science.gov (United States)

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used.

  18. Dual orexin receptor antagonists show distinct effects on locomotor performance, ethanol interaction and sleep architecture relative to gamma-aminobutyric acid-A receptor modulators

    Directory of Open Access Journals (Sweden)

    Andres D. Ramirez

    2013-12-01

    Full Text Available Dual orexin receptor antagonists (DORAs are a potential treatment for insomnia that function by blocking both the orexin 1 and orexin 2 receptors. The objective of the current study was to further confirm the impact of therapeutic mechanisms targeting insomnia on locomotor coordination and ethanol interaction using DORAs and gamma-aminobutyric acid (GABA-A receptor modulators of distinct chemical structure and pharmacologic properties in the context of sleep-promoting potential. The current study compared rat motor co-ordination after administration of DORAs, DORA-12 and almorexant, and GABA-A receptor modulators, zolpidem, eszopiclone and diazepam, alone or each in combination with ethanol. Motor performance was assessed by measuring time spent walking on a rotarod apparatus. Zolpidem, eszopiclone and diazepam (0.3–30 mg/kg administered orally [PO] impaired rotarod performance in a dose-dependent manner. Furthermore, all three GABA-A receptor modulators potentiated ethanol- (0.25–1.25 g/kg induced impairment on the rotarod. By contrast, neither DORA-12 (10–100 mg/kg, PO nor almorexant (30–300 mg/kg, PO impaired motor performance alone or in combination with ethanol. In addition, distinct differences in sleep architecture were observed between ethanol, GABA-A receptor modulators (zolpidem, eszopiclone and diazepam and DORA-12 in electroencephalogram studies in rats. These findings provide further evidence that orexin receptor antagonists have an improved motor side-effect profile compared with currently available sleep-promoting agents based on preclinical data and strengthen the rationale for further evaluation of these agents in clinical development.

  19. At last, a truly selective EP2 receptor antagonist

    OpenAIRE

    Birrell, Mark A.; Nials, Anthony T.

    2011-01-01

    Ever since the discovery of prostaglandin E2 (PGE2), this lipid mediator has been the focus of intense research. The diverse biological effects of PGE2 are due, at least in part, to the existence of four distinct receptors (EP1–4). This can complicate the analysis of the biological effects produced by PGE2. While there are currently selective pharmacological tools to explore the roles of the EP1,3,4 receptors in cellular and tissue responses, analysis of EP2 receptor-induced responses has bee...

  20. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists.

    Science.gov (United States)

    Meini, Stefania; Cucchi, Paola; Bellucci, Francesca; Catalani, Claudio; Faiella, Angela; Rotondaro, Luigi; Quartara, Laura; Giolitti, Alessandro; Maggi, Carlo Alberto

    2004-02-15

    Combining site-directed mutagenesis with information obtained from molecular modelling of the bradykinin (BK) human B2 receptor (hB2R) as derived from the bovine rhodopsin crystal structure [Science 289 (2000) 739], we previously defined a putative binding mode for the non-peptide B2 receptor antagonists, FR173657 and LF16-0687 [Can J Physiol Pharmacol 80 (2002) 303]. The present work is aimed to define the specific role of the quinoline moiety in the pharmacophore of these non-peptide antagonists. The effect of the mutations I110A, L114A (TM, transmembrane 3), W256A (TM6), F292A, Y295A and Y295F (TM7) was evaluated. None of the mutations affected the binding interaction of peptide ligands: the agonist BK and the peptide antagonist MEN 11270. The affinities in competing for [3H]-BK binding and in blocking the BK-induced IP production by the non-peptide antagonists LF16-0687 and FR173657 at the wild type and mutant receptors were analysed. While the affinities of LF16-0687 and FR173657 were crucially decreased at the I110A, Y295A, and Y295F mutants, the W256A mutation affected the affinity of the LF16-0687 only. The important contribution of the quinoline moiety was shown by the inability of an analogue of LF16-0687, lacking this moiety, to affect BK binding at the wild type receptor. On the other hand, the benzamidine group did not interact with mutated residues, since LF16-0687 analogues without this group or with an oxidated benzamidine displayed pairwise loss of affinity on wild type and mutated receptors. Further differences between FR173657 and LF16-0687 were highlighted at the I110 and Y295 mutants when comparing binding (pK(i)) and functional antagonist (pKB) affinity. First, the I110A mutation similarly impaired their binding affinity (250-fold), but at a less extent the antagonist potency of FR173657 only. Second, both the hydroxyl and the phenyl moieties of the Y295 residue had a specific role in the LF16-0687 interaction with the receptor, as

  1. Modification of formalin-induced nociception by different histamine receptor agonists and antagonists.

    Science.gov (United States)

    Farzin, Davood; Nosrati, Farnaz

    2007-01-15

    The present study evaluated the effects of different histamine receptor agonists and antagonists on the nociceptive response in the mouse formalin test. Intracerebroventricular (20-40 microg/mouse i.c.v.) or subcutaneous (1-10 mg/kg s.c.) injection of HTMT (H(1) receptor agonist) elicited a dose-related hyperalgesia in the early and late phases. Conversely, intraperitoneal (20 and 30 mg/kg i.p.) injection of dexchlorpheniramine (H(1) receptor antagonist) was antinociceptive in both phases. At a dose ineffective per se, dexchlorpheniramine (10 mg/kg i.p.) antagonized the hyperalgesia induced by HTMT (40 mug/mouse i.c.v. or 10 mg/kg s.c.). Dimaprit (H(2) receptor agonist, 30 mg/kg i.p.) and ranitidine (H(2) receptor antagonist, 20 and 40 mg/kg i.p.) reduced the nociceptive responses in the early and late phases. No significant change in the antinociceptive activity was found following the combination of dimaprit (30 mg/kg i.p.) with ranitidine (10 mg/kg i.p.). The antinociceptive effect of dimaprit (30 mg/kg i.p.) was prevented by naloxone (5 mg/kg i.p.) in the early phase or by imetit (H(3) receptor agonist, 25 mg/kg i.p.) in both early and late phases. The histamine H(3) receptor agonist imetit was hyperalgesic following i.p. administration of 50 mg/kg. Imetit-induced hyperalgesia was completely prevented by treatment with a dose ineffective per se of thioperamide (H(3) receptor antagonist, 5 mg/kg i.p.). The results suggest that histamine H(1) and H(3) receptor activations increase sensitivity to nociceptive stimulus in the formalin test.

  2. Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice.

    Science.gov (United States)

    Bonaventura, María M; Crivello, Martín; Ferreira, María Laura; Repetto, Martín; Cymeryng, Cora; Libertun, Carlos; Lux-Lantos, Victoria A

    2012-02-29

    γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Identification of three muscarinic receptor subtypes in rat lung using binding studies with selective antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Fryer, A.D.; El-Fakahany, E.E. (Univ. of Maryland, Baltimore (USA))

    1990-01-01

    Heterogeneity of the muscarinic receptor population in the rat central and peripheral lung was found in competition binding experiments against ({sup 3}H)quinuclidinyl benzilate (({sup 3}H)QNB) using the selective antagonists pirenzepine, AF-DX 116 and hexahydrosiladifenidol (HHSiD). Pirenzepine displaced ({sup 3}H)QNB with low affinity from preparations of central airways indicating the absence of M{sub 1} receptors in the trachea and bronchi. Muscarinic receptors in the central airways are comprised of both M{sub 2} and M{sub 3} receptors since AF-DX 116, an M{sub 2}-selective antagonist, bound with high affinity to 70% of the available sites while HHSiD, an M{sub 3}-selective antagonist bound with high affinity to the remaining binding sites. In the peripheral lung, pirenzepine bound with high affinity to 14% of the receptor population, AF-DX 116 bound with high affinity 79% of the binding sites while HHSiD bound with high affinity to 18% of the binding sites. The presence of M{sub 1} receptors in the peripheral airways but not in the central airways was confirmed using ({sup 3}H)telenzepine, an M{sub 1} receptor ligand. ({sup 3}H)Telenzepine showed specific saturable binding to 8% of ({sup 3}H)QNB labeled binding sites in homogenates of rat peripheral lung, while there was no detectable specific binding in homogenates of rat trachea or heart.

  4. Kinin B1 receptor antagonists inhibit diabetes-induced hyperalgesia in mice.

    Science.gov (United States)

    Gabra, Bichoy H; Sirois, Pierre

    2003-02-01

    Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, neuropathy, hypertension and hyperalgesia. The bradykinin B(1) receptors (BKB(1)-R) were recently found to be upregulated alongside the development of type 1 diabetes and to be involved in its complications. Kinins are important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of a selective BKB(1)-R agonist desArg(9)-BK (DBK) and two selective receptor antagonists, the R-715 (Ac-Lys-[D-beta Nal(7), Ile(8)] desArg(9)-BK) and the R-954 (Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)] desArg(9)-BK) on diabetic hyperalgesia. Type 1 diabetes was induced in male CD-1 mice via a single injection of streptozotocin (STZ, 200mg/kg, i.p.), one week before the test. Nociception, a measure of hyperalgesia, was assessed using the plantar stimulation (Hargreaves) and the tail-immersion tests. The induction of type 1 diabetes provoked a significant hyperalgesic activity in diabetic mice, causing an 11% decrease in plantar stimulation reaction time and 13% decrease in tail-immersion reaction time, compared to normal mice. Following acute administration of R-715 (100-600 microg/kg, i.p.), or R-954 (50-400 microg/kg, i.p.), the STZ-induced hyperalgesic activity was blocked in a dose-dependent manner and the hot plate and tail-immersion latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of DBK (400 microg/kg, i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg/kg, i.p.) and R-954 (0.8-1.2mg/kg, i.p.). These results provide further evidence for the implication of the BKB(1)-R in type 1 diabetic hyperalgesia and suggest a novel

  5. Optimizing control of acromegaly: integrating a growth hormone receptor antagonist into the treatment algorithm.

    Science.gov (United States)

    Clemmons, David R; Chihara, Kazuo; Freda, Pamela U; Ho, Ken K Y; Klibanski, Anne; Melmed, Shlomo; Shalet, Stephen M; Strasburger, Christian J; Trainer, Peter J; Thorner, Michael O

    2003-10-01

    Acromegaly is associated with significant morbidities and a 2- to 3-fold increase in mortality because of the excessive metabolic action of GH and IGF-I, a marker of GH output. Reductions in morbidity correspond with decreases in IGF-I, and mortality is lowered following normalization of IGF-I or GH levels. Therefore, this has become an important end point. Current guidelines for the treatment of acromegaly have not considered recent advances in medical therapy, in particular, the place of pegvisomant, a GH receptor antagonist. Treatment goals include normalizing biochemical markers, controlling tumor mass, preserving pituitary function, and relieving signs and symptoms. Surgery reduces tumor volume and is considered first-line therapy. Radiation reduces tumor volume and GH and IGF-I levels, but the onset of action is slow and hypopituitarism typically develops. Therefore, pharmacotherapy is often used following surgery or as first-line therapy for nonresectable tumors. Dopamine agonists can be considered in patients exhibiting minimal disease or those with GH-prolactin-cosecreting tumors but will not achieve hormone normalization in most patients. Somatostatin analogs effectively suppress GH and IGF-I in most patients, but intolerance (e.g. diarrhea, cramping, gallstones) can occur. Pegvisomant, the newest therapeutic option, blocks GH action at peripheral receptors, normalizes IGF-I levels, reduces signs and symptoms, and corrects metabolic defects. Pegvisomant does not appear to affect tumor size and has few adverse effects. Pegvisomant is the most effective drug treatment for acromegaly in normalizing IGF-I and producing a clinical response; it is the preferred agent in patients resistant to or intolerant of somatostatin analogs.

  6. Rational Design of Potent Antagonists to the Human Growth Hormone Receptor

    Science.gov (United States)

    Fuh, Germaine; Cunningham, Brian C.; Fukunaga, Rikiro; Nagata, Shigekazu; Goeddel, David V.; Wells, James A.

    1992-06-01

    A hybrid receptor was constructed that contained the extracellular binding domain of the human growth hormone (hGH) receptor linked to the transmembrane and intracellular domains of the murine granulocyte colony-stimulating factor receptor. Addition of hGH to a myeloid leukemia cell line (FDC-P1) that expressed the hybrid receptor caused proliferation of these cells. The mechanism for signal transduction of the hybrid receptor required dimerization because monoclonal antibodies to the hGH receptor were agonists whereas their monovalent fragments were not. Receptor dimerization occurs sequentially-a receptor binds to site 1 on hGH, and then a second receptor molecule binds to site 2 on hGH. On the basis of this sequential mechanism, which may occur in many other cytokine receptors, inactive hGH analogs were designed that were potent antagonists to hGH-induced cell proliferation. Such antagonists could be useful for treating clinical conditions of hGH excess, such as acromegaly.

  7. (-) Arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β.

    Science.gov (United States)

    Ogungbe, Ifedayo Victor; Crouch, Rebecca A; Demeritte, Teresa

    2014-11-24

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (-) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor.

  8. (−) Arctigenin and (+) Pinoresinol Are Antagonists of the Human Thyroid Hormone Receptor β

    Science.gov (United States)

    2015-01-01

    Lignans are important biologically active dietary polyphenolic compounds. Consumption of foods that are rich in lignans is associated with positive health effects. Using modeling tools to probe the ligand-binding pockets of molecular receptors, we found that lignans have high docking affinity for the human thyroid hormone receptor β. Follow-up experimental results show that lignans (−) arctigenin and (+) pinoresinol are antagonists of the human thyroid hormone receptor β. The modeled complexes show key plausible interactions between the two ligands and important amino acid residues of the receptor. PMID:25383984

  9. Discovery of Potent and Highly Selective A2B Adenosine Receptor Antagonist Chemotypes.

    Science.gov (United States)

    El Maatougui, Abdelaziz; Azuaje, Jhonny; González-Gómez, Manuel; Miguez, Gabriel; Crespo, Abel; Carbajales, Carlos; Escalante, Luz; García-Mera, Xerardo; Gutiérrez-de-Terán, Hugo; Sotelo, Eddy

    2016-03-10

    Three novel families of A2B adenosine receptor antagonists were identified in the context of the structural exploration of the 3,4-dihydropyrimidin-2(1H)-one chemotype. The most appealing series contain imidazole, 1,2,4-triazole, or benzimidazole rings fused to the 2,3-positions of the parent diazinone core. The optimization process enabled identification of a highly potent (3.49 nM) A2B ligand that exhibits complete selectivity toward A1, A2A, and A3 receptors. The results of functional cAMP experiments confirmed the antagonistic behavior of representative ligands. The main SAR trends identified within the series were substantiated by a molecular modeling study based on a receptor-driven docking model constructed on the basis of the crystal structure of the human A2A receptor.

  10. AMPA and GABA receptor antagonists and their interaction in rats with a genetic form of absence epilepsy

    NARCIS (Netherlands)

    Kaminski, R.M.; Rijn, C.M. van; Turski, W.A.; Czuczwar, S.J.; Luijtelaar, E.L.J.M. van

    2001-01-01

    The effects of combined and single administration of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, 7,8-methylenedioxy-1-(4-aminophenyl)-4-methyl-3-acetyl-4,5-dihydro-2,3 -benzodiazepine (LY 300164), and of the GABAB receptor antagonist -aminopropyl-n-butyl-phosp

  11. Histamine H3 receptor antagonist decreases cue-induced alcohol reinstatement in mice.

    Science.gov (United States)

    Nuutinen, Saara; Mäki, Tiia; Rozov, Stanislav; Bäckström, Pia; Hyytiä, Petri; Piepponen, Petteri; Panula, Pertti

    2016-07-01

    We have earlier found that the histamine H3 receptor (H3R) antagonism diminishes motivational aspects of alcohol reinforcement in mice. Here we studied the role of H3Rs in cue-induced reinstatement of alcohol seeking in C57BL/6J mice using two different H3R antagonists. Systemic administration of H3R antagonists attenuated cue-induced alcohol seeking suggesting that H3R antagonists may reduce alcohol craving. To understand how alcohol affects dopamine and histamine release, a microdialysis study was performed on C57BL/6J mice and the levels of histamine, dopamine and dopamine metabolites were measured in the nucleus accumbens. Alcohol administration was combined with an H3R antagonist pretreatment to reveal whether modulation of H3R affects the effects of alcohol on neurotransmitter release. Alcohol significantly increased the release of dopamine in the nucleus accumbens but did not affect histamine release. Pretreatment with H3R antagonist ciproxifan did not modify the effect of alcohol on dopamine release. However, histamine release was markedly increased with ciproxifan. In conclusion, our findings demonstrate that H3R antagonism attenuates cue-induced reinstatement of alcohol seeking in mice. Alcohol alone does not affect histamine release in the nucleus accumbens but H3R antagonist instead increases histamine release significantly suggesting that the mechanism by which H3R antagonist inhibits alcohol seeking found in the present study and the decreased alcohol reinforcement, reward and consumption found earlier might include alterations in the histaminergic neurotransmission in the nucleus accumbens. These findings imply that selective antagonists of H3Rs could be a therapeutic strategy to prevent relapse and possibly diminish craving to alcohol use. This article is part of the Special Issue entitled 'Histamine Receptors'.

  12. Synthesis and dual histamine H₁ and H₂ receptor antagonist activity of cyanoguanidine derivatives.

    Science.gov (United States)

    Sadek, Bassem; Alisch, Rudi; Buschauer, Armin; Elz, Sigurd

    2013-11-15

    Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

  13. Synthesis and Dual Histamine H1 and H2 Receptor Antagonist Activity of Cyanoguanidine Derivatives

    Directory of Open Access Journals (Sweden)

    Bassem Sadek

    2013-11-01

    Full Text Available Premedication with a combination of histamine H1 receptor (H1R and H2 receptor (H2R antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14–35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the “urea equivalent” of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R and the isolated spontaneously beating right atrium (H2R of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21, and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33, N-cyano-N'-[2-[[(2-guanidino-4-thiazolylmethyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl-N-(pyridyl-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum and 7.73 (H2R, atrium and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R and 6.61 (H2R were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.

  14. Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    Science.gov (United States)

    Roecker, Anthony J; Cox, Christopher D; Coleman, Paul J

    2016-01-28

    Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.

  15. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease

    DEFF Research Database (Denmark)

    Currie, Gemma; Taylor, Alison H M; Fujita, Toshiro

    2016-01-01

    BACKGROUND: Hypertension and proteinuria are critically involved in the progression of chronic kidney disease. Despite treatment with renin angiotensin system inhibition, kidney function declines in many patients. Aldosterone excess is a risk factor for progression of kidney disease. Hyperkalaemia...... is a concern with the use of mineralocorticoid receptor antagonists. We aimed to determine whether the renal protective benefits of mineralocorticoid antagonists outweigh the risk of hyperkalaemia associated with this treatment in patients with chronic kidney disease. METHODS: We conducted a meta......-analysis investigating renoprotective effects and risk of hyperkalaemia in trials of mineralocorticoid receptor antagonists in chronic kidney disease. Trials were identified from MEDLINE (1966-2014), EMBASE (1947-2014) and the Cochrane Clinical Trials Database. Unpublished summary data were obtained from investigators...

  16. Pathophysiology of the cysteinyl leukotrienes and effects of leukotriene receptor antagonists in asthma

    DEFF Research Database (Denmark)

    Bisgaard, H

    2001-01-01

    Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability, ...... antagonists are additive with those of beta agonists. These data provide strong support for the use of leukotriene receptor antagonists for treating asthma.......Cysteinyl leukotrienes, synthesized de novo from cell membrane phospholipids, are proinflammatory mediators that play an important role in the pathophysiology of asthma. These mediators are among the most potent of bronchoconstrictors and cause vasodilation, increased microvascular permeability...... ciliary motility, which may hinder mucociliary clearance. Asthmatic patients demonstrate increased production of cysteinyl leukotrienes during naturally occurring asthma and acute asthma attacks as well as after allergen and exercise challenge. The leukotriene receptor antagonists montelukast, zafirlukast...

  17. Remote functionalization of SCH 39166: discovery of potent and selective benzazepine dopamine D1 receptor antagonists.

    Science.gov (United States)

    Sasikumar, T K; Burnett, Duane A; Greenlee, William J; Smith, Michelle; Fawzi, Ahmad; Zhang, Hongtao; Lachowicz, Jean E

    2010-02-01

    A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.

  18. Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

    OpenAIRE

    de Lorenzi, F G; Bridal, T R; Spinelli, W

    1994-01-01

    1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rect...

  19. Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.

    Science.gov (United States)

    Li, Wencheng; Sullivan, Michelle N; Zhang, Sheng; Worker, Caleb J; Xiong, Zhenggang; Speth, Robert C; Feng, Yumei

    2015-02-01

    We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension. © 2014 American Heart Association, Inc.

  20. Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

    DEFF Research Database (Denmark)

    Madsen, U; Sløk, F A; Stensbøl, T B;

    2000-01-01

    We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4......-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic...... excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2...

  1. Bartonella quintana lipopolysaccharide is a natural antagonist of Toll-like receptor 4.

    NARCIS (Netherlands)

    Popa, C.; Abdollahi-Roodsaz, S.; Joosten, L.A.B.; Takahashi, N.; Sprong, T.; Matera, G.; Liberto, M.C.; Foca, A.; Deuren, M. van; Kullberg, B.J.; Berg, W.B. van den; Meer, J.W.M. van der; Netea, M.G.

    2007-01-01

    Bartonella quintana is a gram-negative microorganism that causes trench fever and chronic bacteremia. B. quintana lipopolysaccharide (LPS) was unable to induce the production of proinflammatory cytokines in human monocytes. Interestingly, B. quintana LPS is a potent antagonist of Toll-like receptor

  2. Luteinizing hormone-releasing hormone receptor antagonist may reduce postmenopausal flushing

    NARCIS (Netherlands)

    Gastel, P. van; Zanden, M. van der; Telting, D.; Filius, M.; Bancsi, L.; Boer, H. de

    2012-01-01

    OBJECTIVE: Hormone therapy (HT) is the most effective treatment of postmenopausal (PMP) flushing; however, its use is often contraindicated. As an alternative option, we explored the efficacy of the luteinizing hormone-releasing hormone (LHRH) receptor antagonist cetrorelix in women with severe PMP

  3. Bicyclams, selective antagonists of the human chemokine receptor CXCR4, potently inhibit feline immunodeficiency virus replication

    NARCIS (Netherlands)

    Horzinek, M.C.; Egberink, H.F.; Clercq, E. de; Vliet, A.L.W. van; Balzarini, J.; Bridger, G.J.; Henson, G.; Schols, D.

    1999-01-01

    Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when evalua

  4. Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators

    Science.gov (United States)

    2009-01-01

    Netherlands ) (see appendices). Small Molecule Inhibitors of the Androgen Receptor Transcriptional Activity for Prostate Cancer Drug Discovery...peritoneal injection, tail injection, oral gavage, retro-orbital blood sampling, isoflurane anesthesia, CO2 euthanasia , cardiac stick, organ harvesting...Discovery Poster Award, Androgens 2008 Meeting, Rotterdam (The Netherlands ), October 2008 Novel Small Molecules Antagonists of the Interaction of

  5. Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

    DEFF Research Database (Denmark)

    Jepsen, Tue H.; Jensen, Anders A.; Lund, Mads Henrik;

    2014-01-01

    Dihydro-β-erythroidine (DHβE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHβE in complex with an ACh binding protein, we detail the design, synthesis...

  6. Predictors of Congestive Heart Failure after Treatment with an Endothelin Receptor Antagonist

    NARCIS (Netherlands)

    Hoekman, Jamo; Lambers Heerspink, Hiddo; Viberti, Giancarlo; Green, Damien; Mann, Johannes F. E.; de Zeeuw, Dick

    2014-01-01

    Background and objectives The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death (ASCEND) trial tested the renoprotective effect of the endothelin receptor antagonist avosentan in patients with diabetes and nephropathy, but the study was terminated due to an excess o

  7. Effect of the cannabinoid receptor-1 antagonist rimonabant on lipolysis in rats

    DEFF Research Database (Denmark)

    Mølhøj, Signe; Hansen, Harald S; Schweiger, Martina

    2010-01-01

    The cannabinoid receptor 1 antagonist, rimonabant, reduces food intake and body weight, but contradictory findings have been reported as to whether the weight-reducing effect is fully accounted for by the reduced food intake or if rimonabant also mediates a lipolytic effect. In the present study...

  8. I. Effects of a Dopamine Receptor Antagonist on Fathead Minnow, Pimephales promelas ,Reproduction

    Science.gov (United States)

    This study used a 21 d fathead minnow (Pimephales promelas) reproduction assay to test the hypothesis that exposure to the dopamine 2 receptor (D2R) antagonist, haloperidol, would impair fish reproduction. Additionally, a 96 h experiment with fathead minnows and zebrafish (Danio ...

  9. Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

    DEFF Research Database (Denmark)

    Petersen, Ida Nymann; Crestey, François; Jensen, Anders A

    2015-01-01

    Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers...

  10. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction : integrating evidence into clinical practice

    NARCIS (Netherlands)

    Zannad, Faiez; Stough, Wendy Gattis; Rossignol, Patrick; Bauersachs, Johann; McMurray, John J. V.; Swedberg, Karl; Struthers, Allan D.; Voors, Adriaan A.; Ruilope, Luis M.; Bakris, George L.; O'Connor, Christopher M.; Gheorghiade, Mihai; Mentz, Robert J.; Cohen-Solal, Alain; Maggioni, Aldo P.; Beygui, Farzin; Filippatos, Gerasimos S.; Massy, Ziad A.; Pathak, Atul; Pina, Ileana L.; Sabbah, Hani N.; Sica, Domenic A.; Tavazzi, Luigi; Pitt, Bertram

    2012-01-01

    Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection fraction (HFREF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These cl

  11. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

    NARCIS (Netherlands)

    Figueira, A C M; Saidemberg, D M; Telles de Souza, Paulo; Martínez, L; Scanlan, T S; Baxter, J D; Skaf, M S; Palma, M S; Webb, P M; Polikarpov, I

    2011-01-01

    Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains i

  12. Long-term use of aldosterone-receptor antagonists in uncontrolled hypertension: A retrospective analysis

    NARCIS (Netherlands)

    P.M. Jansen (Pieter); K. Verdonk (Koen); B.P. Imholz (Ben); A.H.J. Danser (Jan); A.H. van den Meiracker (Anton)

    2011-01-01

    textabstractBackground. The long-term efficacy of aldosterone-receptor antagonists (ARAs) as add-on treatment in uncontrolled hypertension has not yet been reported. Methods. Data from 123 patients (21 with primary aldosteronism, 102 with essential hypertension) with difficult-to-treat hypertension

  13. Pyrazolo Derivatives as Potent Adenosine Receptor Antagonists: An Overview on the Structure-Activity Relationships

    Directory of Open Access Journals (Sweden)

    Siew Lee Cheong

    2011-01-01

    Full Text Available In the past few decades, medicinal chemistry research towards potent and selective antagonists of human adenosine receptors (namely, A1, A2A, A2B, and A3 has been evolving rapidly. These antagonists are deemed therapeutically beneficial in several pathological conditions including neurological and renal disorders, cancer, inflammation, and glaucoma. Up to this point, many classes of compounds have been successfully synthesized and identified as potent human adenosine receptor antagonists. In this paper, an overview of the structure-activity relationship (SAR profiles of promising nonxanthine pyrazolo derivatives is reported and discussed. We have emphasized the SAR for some representative structures such as pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines; pyrazolo-[3,4-c] or -[4,3-c]quinolines; pyrazolo-[4,3-d]pyrimidinones; pyrazolo-[3,4-d]pyrimidines and pyrazolo-[1,5-a]pyridines. This overview not only clarifies the structural requirements deemed essential for affinity towards individual adenosine receptor subtypes, but it also sheds light on the rational design and optimization of existing structural templates to allow us to conceive new, more potent adenosine receptor antagonists.

  14. N-Oxide analogs of WAY-100635 : new high affinity 5-HT (1A) receptor antagonists

    NARCIS (Netherlands)

    Oberwinkler - Marchais, Sandrine; Nowicki, B; Pike, VW; Halldin, C; Sandell, J; Chou, YH; Gulyas, B; Brennum, LT; Farde, L; Wikstrom, H V

    2005-01-01

    WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radiol

  15. N-Oxide analogs of WAY-100635 : new high affinity 5-HT1A receptor antagonists

    NARCIS (Netherlands)

    Marchais-Oberwinkler, S; Nowicki, B; Pike, VW; Halldin, C; Sandell, J; Chou, YH; Gulyas, B; Brennum, LT; Farde, L; Wikstrom, HV

    2005-01-01

    WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radiol

  16. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2009-01-01

    OBJECTIVE: Interleukin (IL)-1 impairs insulin secretion and induces beta-cell apoptosis. Pancreatic beta-cell IL-1 expression is increased and interleukin-1 receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes. Treatment with recombinant IL-1Ra improves glycemia and beta...

  17. Evidence for homogeneity of thromboxane A2 receptor using structurally different antagonists.

    Science.gov (United States)

    Swayne, G T; Maguire, J; Dolan, J; Raval, P; Dane, G; Greener, M; Owen, D A

    1988-08-01

    Nine structurally dissimilar thromboxane antagonists (SQ 29548, ICI 185282, AH 23848, BM 13505 (Daltroban), BM 13177 (Sulotroban), SK&F 88046, L-636499, L-640035 and a Bayer compound SK&F 47821) were studied for activity as thromboxane A2 receptor antagonists. The assays used were inhibition of responses induced by the thromboxane mimetic, U46619, on human washed platelet aggregation, rabbit platelet aggregation, rabbit aortic strip contraction, anaesthetised guinea-pig bronchoconstriction, and a radio-labelled ligand (125I-PTA-OH) binding assay as a measure of affinity for the human platelet receptor. The results of the present study, with activities spanning at least four orders of magnitude along with statistically significant correlations (at least P less than 0.01), strongly suggests that between assays, antagonists and species a homogenous population of thromboxane A2 receptors exists. This finding is in contrast to those of a close series of 13-azapinane antagonists studied by other workers which have suggested receptor heterogeneity.

  18. Effect of the Urotensin Receptor Antagonist Palosuran in Hypertensive Patients With Type 2 Diabetic Nephropathy

    NARCIS (Netherlands)

    L. Vogt; C. Chiurchiu; H. Chadha-Boreham; P. Danaietash; J. Dingemanse; S. Hadjadj; H. Krum; G. Navis; E. Neuhart; A.I. Parvanova; P. Ruggenenti; A.J. Woittiez; R. Zimlichman; G. Remuzzi; D. de Zeeuw

    2010-01-01

    The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion an

  19. Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries

    NARCIS (Netherlands)

    L. Edvinsson (Lars); K.Y. Chan (Kayi); S. Eftekhari; E. Nilsson (Elisabeth); R. de Vries (René); H. Säveland (Hans); C.M.F. Dirven (Clemens); A.H.J. Danser (Jan)

    2010-01-01

    textabstractIntroduction: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. Materials and methods: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-in

  20. Design, synthesis, and biological evaluation of 4-phenylpyrrole derivatives as novel androgen receptor antagonists.

    Science.gov (United States)

    Yamamoto, Satoshi; Matsunaga, Nobuyuki; Hitaka, Takenori; Yamada, Masami; Hara, Takahito; Miyazaki, Junichi; Santou, Takashi; Kusaka, Masami; Yamaoka, Masuo; Kanzaki, Naoyuki; Furuya, Shuichi; Tasaka, Akihiro; Hamamura, Kazumasa; Ito, Mitsuhiro

    2012-01-01

    A series of 4-phenylpyrrole derivatives D were designed, synthesized, and evaluated for their potential as novel orally available androgen receptor antagonists therapeutically effective against castration-resistant prostate cancers. 4-Phenylpyrrole compound 1 exhibited androgen receptor (AR) antagonistic activity against T877A and W741C mutant-type ARs as well as wild-type AR. An arylmethyl group incorporated into compound 1 contributed to enhancement of antagonistic activity. Compound 4n, 1-{[6-chloro-5-(hydroxymethyl)pyridin-3-yl]methyl}-4-(4-cyanophenyl)-2,5-dimethyl-1H-pyrrole-3-carbonitrile exhibited inhibitory effects on tumor cell growth against the bicalutamide-resistant LNCaP-cxD2 cell line as well as the androgen receptor-dependent JDCaP cell line in a mouse xenograft model. These results demonstrate that this series of pyrrole compounds are novel androgen receptor antagonists with efficacy against prostate cancer cells, including castration-resistant prostate cancers such as bicalutamide-resistant prostate cancer.

  1. Analysis of Agonist and Antagonist Effects on Thyroid Hormone Receptor Conformation by Hydrogen/Deuterium Exchange

    NARCIS (Netherlands)

    Figueira, A C M; Saidemberg, D M; Telles de Souza, Paulo; Martínez, L; Scanlan, T S; Baxter, J D; Skaf, M S; Palma, M S; Webb, P M; Polikarpov, I

    Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains

  2. Cannabinoid receptor antagonists and the metabolic syndrome: Novel promising therapeutical approaches.

    Science.gov (United States)

    Cervino, C; Pasquali, R; Pagotto, U

    2007-01-01

    Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

  3. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.

    Science.gov (United States)

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J; Allan, Stuart M

    2016-03-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.

  4. Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

    Directory of Open Access Journals (Sweden)

    Adrian E. Roitberg

    2008-06-01

    Full Text Available Estrogen receptors (ER are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

  5. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Haga, Kazuko; Kruse, Andrew C.; Asada, Hidetsugu; Yurugi-Kobayashi, Takami; Shiroishi, Mitsunori; Zhang, Cheng; Weis, William I.; Okada, Tetsuji; Kobilka, Brian K.; Haga, Tatsuya; Kobayashi, Takuya (Stanford-MED); (Kyoto); (Gakushuin); (Kyushu)

    2012-03-15

    The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.

  6. Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

    Directory of Open Access Journals (Sweden)

    Nappi J

    2011-06-01

    Full Text Available Jean M Nappi, Adam SiegClinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, Charleston, SC, USAAbstract: Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms

  7. Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity.

    Science.gov (United States)

    Kostyalik, Diána; Kátai, Zita; Vas, Szilvia; Pap, Dorottya; Petschner, Péter; Molnár, Eszter; Gyertyán, István; Kalmár, Lajos; Tóthfalusi, László; Bagdy, Gyorgy

    2014-03-01

    Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

  8. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.

    Science.gov (United States)

    Heidbreder, Christian A; Newman, Amy H

    2010-02-01

    Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

  9. Medicinal chemistry of small molecule CCR5 antagonists for blocking HIV-1 entry: a review of structural evolution.

    Science.gov (United States)

    Tian, Ye; Zhang, Dujuan; Zhan, Peng; Liu, Xinyong

    2014-01-01

    CCR5, a member of G protein-coupled receptors superfamily, plays an important role in the HIV-1 entry process. Antagonism of this receptor finally leads to the inhibition of R5 strains of HIV entry into the human cells. The identification of CCR5 antagonists as antiviral agents will provide more option for HAART. Now, more than a decade after the first small molecule CCR5 inhibitor was discovered, great achievements have been made. In this article, we will give a brief introduction of several series of small molecule CCR5 antagonists, focused on their appealing structure evolution, essential SAR information and thereof the enlightenment of strategies on CCR5 inhibitors design.

  10. Prevention of Stimulant Induced Euphoria with an Opioid Receptor Antagonist

    Science.gov (United States)

    2015-10-01

    peers, deficits in the interactions with peers and superiors, emotional impulsivity that could lead to low self esteem , substance abuse, criminality...Young Adults With ADHD. J Am Acad Child Adolesc Psychiatry. 50(6): p. 543- 53. 12. Zhu, J., et al., Methylphenidate and mu opioid receptor interactions...Sponsor Approved Recorded by / Date 6/14/13 6/14/13 1770201 The blood draw was not completed on Drug Feeling visit after 2 different phlebotomy

  11. Orexin, orexin receptor antagonists and central cardiovascular control

    OpenAIRE

    Carrive, Pascal

    2013-01-01

    Orexin makes an important contribution to the regulation of cardiovascular function. When injected centrally under anesthesia, orexin increases blood pressure, heart rate and sympathetic nerve activity. This is consistent with the location of orexin neurons in the hypothalamus and the distribution of orexin terminals in the central autonomic network. Thus, the two orexin receptors, Ox1R and Ox2R, which have partly overlapping distributions in the brain, are expressed in the sympathetic pregan...

  12. Radiosensitizing Effect of P2X7 Receptor Antagonist on Melanoma in vitro and in vivo.

    Science.gov (United States)

    Tanamachi, Keisuke; Nishino, Keisuke; Mori, Natsuki; Suzuki, Toshihiro; Tanuma, Sei-Ichi; Abe, Ryo; Tsukimoto, Mitsutoshi

    2017-03-24

    Melanoma is highly malignant, and generally exhibits radioresistance, responding poorly to radiation therapy. We previously reported that activation of P2X7, P2Y6, and P2Y12 receptors is involved in the DNA damage response after γ-irradiation of human lung adenocarcinoma A549 cells. However, it is not clear whether these receptors are also involved in the case of melanoma cells, although P2X7 receptor is highly expressed in various cancers, including melanoma. Here, we show that P2X7 receptor antagonist enhances radiation-induced cytotoxicity in B16 melanoma cells in vitro and in vivo. We confirmed that these cells express P2X7 receptor mRNA and exhibit P2X7 receptor-mediated activities, such as ATP-induced pore formation and cytotoxicity. We further examined the radiosensitizing effect of P2X7 receptor antagonist Brilliant Blue G (BBG) in vitro by colony formation assay of B16 cells. γ-Irradiation dose-dependently reduced cell survival, and pretreatment with BBG enhanced the radiation-induced cytotoxicity. BBG pretreatment also decreased the number of DNA repair foci in nuclei, supporting involvement of P2X7 receptor in the DNA damage response. Finally, we investigated the radiosensitizing effect of BBG on B16 melanoma cells inoculated into the hind footpad of C57BL/6 mice. Neither 1 Gy γ-irradiation alone nor BBG alone suppressed the increase of tumor volume, but the combination of irradiation and BBG significantly suppressed tumor growth. Our results suggest that P2X7 receptor antagonist BBG has a radiosensitizing effect in melanoma in vitro and in vivo. BBG, which is used as a food coloring agent, appears to be a promising candidate as a radiosensitizer.

  13. Effects of histamine H(1) receptor antagonists on depressive-like behavior in diabetic mice.

    Science.gov (United States)

    Hirano, Shoko; Miyata, Shigeo; Onodera, Kenji; Kamei, Junzo

    2006-02-01

    We previously reported that streptozotocin-induced diabetic mice showed depressive-like behavior in the tail suspension test. It is well known that the central histaminergic system regulates many physiological functions including emotional behaviors. In this study, we examined the role of the central histaminergic system in the diabetes-induced depressive-like behavior in the mouse tail suspension test. The histamine contents in the hypothalamus were significantly higher in diabetic mice than in non-diabetic mice. The histamine H(1) receptor antagonist chlorpheniramine (1-10 mg/kg, s.c.) dose-dependently and significantly reduced the duration of immobility in both non-diabetic and diabetic mice. In contrast, the selective histamine H(1) receptor antagonists epinastine (0.03-0.3 microg/mouse, i.c.v.) and cetirizine (0.01-0.1 microg/mouse, i.c.v.) dose-dependently and significantly suppressed the duration of immobility in diabetic mice, but not in non-diabetic mice. Spontaneous locomotor activity was not affected by histamine H(1) receptor antagonists in either non-diabetic or diabetic mice. In addition, the number and affinity of histamine H(1) receptors in the frontal cortex were not affected by diabetes. In conclusion, we suggest that the altered neuronal system mediated by the activation of histamine H(1) receptors is involved, at least in part, in the depressive-like behavior seen in diabetic mice.

  14. Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases

    Directory of Open Access Journals (Sweden)

    Samuele Maramai

    2016-10-01

    Full Text Available D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs.A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements.The receptor/multireceptor affinity and functional profiles for the examined compounds has been covered, together with their most significant pharmacological applications.

  15. Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists.

    Science.gov (United States)

    Farzin, Davood; Asghari, Ladan; Nowrouzi, Mahvash

    2002-06-01

    The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.

  16. Serotonin (5-HT3 receptor antagonists for the reduction of symptoms of low anterior resection syndrome

    Directory of Open Access Journals (Sweden)

    Itagaki R

    2014-03-01

    Full Text Available Ryohei Itagaki, Keiji Koda, Masato Yamazaki, Kiyohiko Shuto, Chihiro Kosugi, Atsushi Hirano, Hidehito Arimitsu, Risa Shiragami, Yukino Yoshimura, Masato Suzuki Department of Surgery, Teikyo University Chiba Medical Center, Anesaki, Ichihara, Chiba, Japan Purpose: Serotonin (5-hydroxytryptamine [5-HT]3 receptor antagonists are effective for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D, in which exaggerated intestinal/colonic hypermotility is often observed. Recent studies have suggested that the motility disorder, especially spastic hypermotility, seen in the neorectum following sphincter-preserving operations for rectal cancer may be the basis of the postoperative defecatory malfunction seen in these patients. We investigated the efficacy of 5-HT3 receptor antagonists in patients suffering from severe low anterior resection syndrome. Patients and methods: A total of 25 male patients with complaints of uncontrollable urgency or fecal incontinence following sphincter-preserving operations were enrolled in this study. Defecatory status, assessed on the basis of incontinence score (0–20, urgency grade (0–3, and number of toilet visits per day, was evaluated using a questionnaire before and 1 month after the administration of the 5-HT3 antagonist ramosetron. Results: All the parameters assessed improved significantly after taking ramosetron for 1 month. The effect was more prominent in cases whose anastomotic line was lower, ie, inside the anal canal. Defecatory function was better in patients who commenced ramosetron therapy within 6 months postoperatively, as compared to those who were not prescribed ramosetron for more than 7 months postoperatively. Conclusion: These results suggest that 5-HT3 antagonists are effective for the treatment of low anterior resection syndrome, as in diarrhea-predominant irritable bowel syndrome. The improvement in symptoms is not merely time dependent, but it is related to treatment with 5

  17. Discovery and characterization of non-competitive antagonists of group I metabotropic glutamate receptors.

    Science.gov (United States)

    Gasparini, F; Floersheim, P; Flor, P J; Heinrich, M; Inderbitzin, W; Ott, D; Pagano, A; Stierlin, C; Stoehr, N; Vranesic, I; Kuhn, R

    2001-01-01

    We have investigated the mechanism of inhibition of the new group I mGluR antagonists CPCCOEt and MPEP and determined that both compounds have a non-competitive mode of inhibition. Furthermore using chimeric/mutated receptors constructs we have found that these antagonists act at a novel pharmacological site located in the trans-membrane (TM). Specific non-conserved amino acid residues in the TM domain have been identified which are necessary for the inhibition by CPCCOEt and MPEP of the mGlul and mGlu5 receptors, respectively. Using molecular modeling a model of the TM domain was built for both mGlu1 and mGlu5 receptor subtypes. Docking of CPCCOEt and MPEP into their respective model allowed the modelisation of the novel binding site.

  18. Novel histamine H3-receptor antagonists and partial agonists with a non-aminergic structure

    OpenAIRE

    Nickel, Tobias; Bauer, Ulrich; Schlicker, Eberhard; Kathmann, Markus; Göthert, Manfred; Sasse, Astrid; Stark, Holger; Schunack, Walter

    2001-01-01

    We determined the affinities of eight novel histamine H3-receptor ligands (ethers and carbamates) for H3-receptor binding sites and their agonistic/antagonistic effects in two functional H3-receptor models. The compounds differ from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n-pentyl, 3-methylbutyl and 3,3-dimethylbutyl, respectively.The compounds monophasically inhibited [3H]-Nα-methylhistamine bin...

  19. Dopamine receptor ligands. Part 18: (1) modification of the structural skeleton of indolobenzazecine-type dopamine receptor antagonists.

    Science.gov (United States)

    Robaa, Dina; Enzensperger, Christoph; Abul Azm, Shams El Din; El Khawass, El Sayeda; El Sayed, Ola; Lehmann, Jochen

    2010-03-25

    On the basis of the D(1/5)-selective dopamine antagonist LE 300 (1), an indolo[3,2-f]benzazecine derivative, we changed the annulation pattern of the heterocycles. The target compounds represent novel heterocyclic ring systems. The most constrained indolo[4,3a,3-ef]benzazecine 2 was inactive, but the indolo[4,3a,3-fg]benzazacycloundecene 3 showed antagonistic properties (functional Ca(2+) assay) with nanomolar affinities (radioligand binding) for all dopamine receptor subtypes, whereas the indolo[2,3-f]benzazecine 4 displayed a selectivity profile similar to 3 but with decreased affinities.

  20. Discovery of new SCH 39166 analogs as potent and selective dopamine D1 receptor antagonists.

    Science.gov (United States)

    Qiang, Li; Sasikumar, T K; Burnett, Duane A; Su, Jing; Tang, Haiqun; Ye, Yuanzan; Mazzola, Robert D; Zhu, Zhaoning; McKittrick, Brian A; Greenlee, William J; Fawzi, Ahmad; Smith, Michelle; Zhang, Hongtao; Lachowicz, Jean E

    2010-02-01

    A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.

  1. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan;

    2011-01-01

    and pharmacological character: (1) chemogenomic lead identification through the first, to our knowledge, ligand inference between two different GPCR families, Families A and C; and (2) the discovery of the most selective GPRC6A allosteric antagonists discovered to date. The unprecedented inference of...... pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors...

  2. Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists.

    Science.gov (United States)

    Wilson, David M; Apps, James; Bailey, Nicholas; Bamford, Mark J; Beresford, Isabel J; Brackenborough, Kim; Briggs, Michael A; Brough, Stephen; Calver, Andrew R; Crook, Barry; Davis, Rebecca K; Davis, Robert P; Davis, Susannah; Dean, David K; Harris, Leanne; Heslop, Teresa; Holland, Vicky; Jeffrey, Phillip; Panchal, Terrance A; Parr, Christopher A; Quashie, Nigel; Schogger, Joanne; Sehmi, Sanjeet S; Stean, Tania O; Steadman, Jon G A; Trail, Brenda; Wald, Jeffrey; Worby, Angela; Takle, Andrew K; Witherington, Jason; Medhurst, Andrew D

    2013-12-15

    This Letter describes the discovery of GSK189254 and GSK239512 that were progressed as clinical candidates to explore the potential of H3 receptor antagonists as novel therapies for the treatment of Alzheimer's disease and other dementias. By carefully controlling the physicochemical properties of the benzazepine series and through the implementation of an aggressive and innovative screening strategy that employed high throughput in vivo assays to efficiently triage compounds, the medicinal chemistry effort was able to rapidly progress the benzazepine class of H3 antagonists through to the identification of clinical candidates with robust in vivo efficacy and excellent developability properties.

  3. Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms

    OpenAIRE

    Yu, Liqun; Shen, Hai-Ying; Coelho, Joana E.; Araújo, Inês M.; HUANG, QING-YUAN; Day, Yuan-Ji; Rebola, Nelson; Canas, Paula M.; Rapp, Erica Kirsten; Ferrara, Jarrod; Taylor, Darcie; Müller, Christa E.; Linden, Joel; Cunha, Rodrigo A.; Chen, Jiang-Fan

    2008-01-01

    To investigate whether the motor and neuroprotective effects of adenosine A2A receptor (A2AR) antagonists are mediated by distinct cell types in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease.We used the forebrain A2AR knock-out mice coupled with flow cytometric analyses and intracerebroventricular injection to determine the contribution of A2ARs in forebrain neurons and glial cells to A2AR antagonist-mediated motor and neuroprotective effects.The selecti...

  4. Cheiradone: a vascular endothelial cell growth factor receptor antagonist

    Directory of Open Access Journals (Sweden)

    Ahmed Nessar

    2008-01-01

    Full Text Available Abstract Background Angiogenesis, the growth of new blood vessels from the pre-existing vasculature is associated with physiological (for example wound healing and pathological conditions (tumour development. Vascular endothelial growth factor (VEGF, fibroblast growth factor-2 (FGF-2 and epidermal growth factor (EGF are the major angiogenic regulators. We have identified a natural product (cheiradone isolated from a Euphorbia species which inhibited in vivo and in vitro VEGF- stimulated angiogenesis but had no effect on FGF-2 or EGF activity. Two primary cultures, bovine aortic and human dermal endothelial cells were used in in vitro (proliferation, wound healing, invasion in Matrigel and tube formation and in vivo (the chick chorioallantoic membrane models of angiogenesis in the presence of growth factors and cheiradone. In all cases, the concentration of cheiradone which caused 50% inhibition (IC50 was determined. The effect of cheiradone on the binding of growth factors to their receptors was also investigated. Results Cheiradone inhibited all stages of VEGF-induced angiogenesis with IC50 values in the range 5.20–7.50 μM but did not inhibit FGF-2 or EGF-induced angiogenesis. It also inhibited VEGF binding to VEGF receptor-1 and 2 with IC50 values of 2.9 and 0.61 μM respectively. Conclusion Cheiradone inhibited VEGF-induced angiogenesis by binding to VEGF receptors -1 and -2 and may be a useful investigative tool to study the specific contribution of VEGF to angiogenesis and may have therapeutic potential.

  5. Species differences in the effects of the κ-opioid receptor antagonist zyklophin.

    Science.gov (United States)

    Sirohi, Sunil; Aldrich, Jane V; Walker, Brendan M

    2016-03-01

    We have shown that dysregulation of the dynorphin/kappa-opioid receptor (DYN/KOR) system contributes to escalated alcohol self-administration in alcohol dependence and that KOR antagonists with extended durations of action selectively reduce escalated alcohol consumption in alcohol-dependent animals. As KOR antagonism has gained widespread attention as a potential therapeutic target to treat alcoholism and multiple neuropsychiatric disorders, we tested the effect of zyklophin (a short-acting KOR antagonist) on escalated alcohol self-administration in rats made alcohol-dependent using intermittent alcohol vapor exposure. Following dependence induction, zyklophin was infused centrally prior to alcohol self-administration sessions and locomotor activity tests during acute withdrawal. Zyklophin did not impact alcohol self-administration or locomotor activity in either exposure condition. To investigate the neurobiological basis of this atypical effect for a KOR antagonist, we utilized a κ-, μ-, and δ-opioid receptor agonist-stimulated GTPyS coupling assay to examine the opioid receptor specificity of zyklophin in the rat brain and mouse brain. In rats, zyklophin did not affect U50488-, DAMGO-, or DADLE-stimulated GTPyS coupling, whereas the prototypical KOR antagonist nor-binaltorphimine (norBNI) attenuated U50488-induced stimulation in the rat brain tissue at concentrations that did not impact μ- and δ-receptor function. To reconcile the discrepancy between the present rat data and published mouse data, comparable GTPyS assays were conducted using mouse brain tissue; zyklophin effects were consistent with KOR antagonism in mice. Moreover, at higher concentrations, zyklophin exhibited agonist properties in rat and mouse brains. These results identify species differences in zyklophin efficacy that, given the rising interest in the development of short-duration KOR antagonists, should provide valuable information for therapeutic development efforts.

  6. Halogenation of a capsaicin analogue leads to novel vanilloid TRPV1 receptor antagonists

    Science.gov (United States)

    Appendino, Giovanni; Harrison, Selena; De Petrocellis, Luciano; Daddario, Nives; Bianchi, Federica; Schiano Moriello, Aniello; Trevisani, Marcello; Benvenuti, Francesca; Geppetti, Pierangelo; Di Marzo, Vincenzo

    2003-01-01

    The C-5 halogenation of the vanillyl moiety of resiniferatoxin, an ultrapotent agonist of vanilloid TRPV1 receptors, results in a potent antagonist for these receptors. Here, we have synthesized a series of halogenated derivatives of ‘synthetic capsaicin' (nonanoyl vanillamide=nordihydrocapsaicin) differing for the nature (iodine, bromine–chlorine) and the regiochemistry (C-5, C-6) of the halogenation.The activity of these compounds was investigated on recombinant human TRPV1 receptors overexpressed in HEK-293 cells. None of the six compounds exerted any significant agonist activity, as assessed by measuring their effect on TRPV1-mediated calcium mobilization. Instead, all compounds antagonized, to various extents, the effect of capsaicin in this assay.All 6-halo-nordihydrocapsaicins behaved as competitive antagonists against human TRPV1 according to the corresponding Schild's plots, and were more potent than the corresponding 5-halogenated analogues. The iodo-derivatives were more potent than the bromo- and chloro-derivatives.Using human recombinant TRPV1, 6-iodo-nordihydrocapsaicin (IC50=10 nM against 100 nM capsaicin) was about four times more potent than the prototypical TRPV1 antagonist, capsazepine, and was tested against capsaicin also on native TRPV1 in: (i) rat dorsal root ganglion neurons in culture; (ii) guinea-pig urinary bladder; and (iii) guinea-pig bronchi. In all cases, except for the guinea-pig bronchi, the compound was significantly more potent than capsazepine as a TRPV1 antagonist.In conclusion, 6-iodo-nordihydrocapsaicin, a stable and easily prepared compound, is a potent TRPV1 antagonist and a convenient replacement for capsazepine in most of the in vitro preparations currently used to assess the activity of putative vanilloid receptor agonists. PMID:12922928

  7. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity.

    Science.gov (United States)

    Porter, Richard H P; Jaeschke, Georg; Spooren, Will; Ballard, Theresa M; Büttelmann, Bernd; Kolczewski, Sabine; Peters, Jens-Uwe; Prinssen, Eric; Wichmann, Jürgen; Vieira, Eric; Mühlemann, Andreas; Gatti, Silvia; Mutel, Vincent; Malherbe, Pari

    2005-11-01

    Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] is an atypical anxiolytic agent with unknown molecular target that has previously been demonstrated both in rodents and human to exert anxiolytic activity. Here, we report that fenobam is a selective and potent metabotropic glutamate (mGlu)5 receptor antagonist acting at an allosteric modulatory site shared with 2-methyl-6-phenylethynyl-pyridine (MPEP), the protypical selective mGlu5 receptor antagonist. Fenobam inhibited quisqualate-evoked intracellular calcium response mediated by human mGlu5 receptor with IC(50) = 58 +/- 2 nM. It acted in a noncompetitive manner, similar to MPEP and demonstrated inverse agonist properties, blocking 66% of the mGlu5 receptor basal activity (in an over expressed cell line) with an IC(50) = 84 +/- 13 nM. [(3)H]Fenobam bound to rat and human recombinant receptors with K(d) values of 54 +/- 6 and 31 +/- 4 nM, respectively. MPEP inhibited [(3)H]fenobam binding to human mGlu5 receptors with a K(i) value of 6.7 +/- 0.7 nM, indicating a common binding site shared by both allosteric antagonists. Fenobam exhibits anxiolytic activity in the stress-induced hyperthermia model, Vogel conflict test, Geller-Seifter conflict test, and conditioned emotional response with a minimum effective dose of 10 to 30 mg/kg p.o. Furthermore, fenobam is devoid of GABAergic activity, confirming previous reports that fenobam acts by a mechanism distinct from benzodiazepines. The non-GABAergic activity of fenobam, coupled with its robust anxiolytic activity and reported efficacy in human in a double blind placebo-controlled trial, supports the potential of developing mGlu5 receptor antagonists with an improved therapeutic window over benzodiazepines as novel anxiolytic agents.

  8. Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats.

    Science.gov (United States)

    Wesołowska, Anna

    2007-01-01

    The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action.

  9. Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.

    Science.gov (United States)

    Maraschin, Jhonatan Christian; Almeida, Camila Biesdorf; Rangel, Marcel Pereira; Roncon, Camila Marroni; Sestile, Caio César; Zangrossi, Hélio; Graeff, Frederico Guilherme; Audi, Elisabeth Aparecida

    2017-06-01

    Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1A receptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5-HT1A-R or the μ-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT1A-R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT1A-R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT1A-R modulation, independently of MOR. Because former results indicate that the 5-HT1A-R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Cannabinoid-1 receptor antagonists in type-2 diabetes.

    Science.gov (United States)

    Scheen, André J

    2007-12-01

    Type-2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a risk of major cardiovascular disease. Several animal and human observations suggest that the endocannabinoid system is over-active in the presence of abdominal obesity and/or diabetes. Both central and peripheral endocannabinoid actions, via the activation of CB1 receptors, promote weight gain and associated metabolic changes. Rimonabant, the first selective CB(1) receptor blocker in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance index and C-reactive protein levels, and to increase high-density lipoprotein (HDL) cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in HbA1c levels was observed in metformin- or sulphonylurea-treated patients with type-2 diabetes and in drug-naïve diabetic patients. Almost half of the metabolic changes, including HbA1c reduction, could not be explained by weight loss, suggesting that there are direct peripheral effects. Rimonabant was generally well-tolerated, and the safety profile was similar in diabetic and non-diabetic patients, with a higher incidence of depressed mood disorders, nausea and dizziness. In conclusion, the potential role of rimonabant in overweight/obese patients with type-2 diabetes and at high risk of cardiovascular disease deserves much consideration.

  11. Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Kanakeswary Karisnan

    Full Text Available Chorioamnionitis (inflammation of the fetal membranes is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA lipopolysaccharide (LPS is orchestrated via interleukin 1 (IL-1. We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra (Anakinra; 100 mg or saline (Sal 3 h prior to second IA injections of LPS (4 mg or Sal at 119d gestational age (GA. Preterm lambs were killed after delivery at 121d GA (term = 150 d. Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group was 25% lower than in control lambs (Sal/Sal group; p=0.025. LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

  12. Latent N-methyl-D-aspartate receptors in the recurrent excitatory pathway between hippocampal CA1 pyramidal neurons: Ca(2+)-dependent activation by blocking A1 adenosine receptors.

    Science.gov (United States)

    Klishin, A; Tsintsadze, T; Lozovaya, N; Krishtal, O

    1995-01-01

    When performed at increased external [Ca2+]/[Mg2+] ratio (2.5 mM/0.5 mM), temporary block of A1 adenosine receptors in hippocampus [by 8-cyclopentyltheophylline (CPT)] leads to a dramatic and irreversible change in the excitatory postsynaptic current (EPSC) evoked by Schaffer collateral/commissural (SCC) stimulation and recorded by in situ patch clamp in CA1 pyramidal neurons. The duration of the EPSC becomes stimulus dependent, increasing with increase in stimulus strength. The later occurring component of the EPSC is carried through N-methyl-D-aspartate (NMDA) receptor-operated channels but disappears under either the NMDA antagonist 2-amino-5-phosphonovaleric acid (APV) or the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings indicate that the late component of the SCC-evoked EPSC is polysynaptic: predominantly non-NMDA receptor-mediated SCC inputs excite CA1 neurons that recurrently excite each other by predominantly NDMA receptor-mediated synapses. These recurrent connections are normally silent but become active after CPT treatment, leading to enhancement of the late component of the EPSC. The activity of these connections is maintained for at least 2 hr after CPT removal. When all functional NMDA receptors are blocked by dizocilpine maleate (MK-801), subsequent application of CPT leads to a partial reappearance of NMDA receptor-mediated EPSCs evoked by SCC stimulation, indicating that latent NMDA receptors are recruited. Altogether, these findings indicate the existence of a powerful system of NMDA receptor-mediated synaptic contacts in SCC input to hippocampal CA1 pyramidal neurons and probably also in reciprocal connections between these neurons, which in the usual preparation are kept latent by activity of A1 receptors. PMID:8618915

  13. Opioid Receptor Antagonists in the Treatment of Alcoholism.

    Science.gov (United States)

    Serecigni, Josep Guardia

    2015-09-29

    Objetivos: A partir de los recientes progresos en la farmacoterapia del alcoholismo, hemos efectuado una revisión sobre los fármacos antagonistas de los receptores opioides, que tienen aprobada la indicación para el tratamiento del alcoholismo, como son naltrexona y nalmefeno. Metodología: Hemos revisado más de 100 publicaciones sobre péptidos y receptores opioides, el efecto de los fármacos antagonistas de los receptores opioides sobre el consumo de alcohol, tanto en animales como en humanos, tanto en el laboratorio como para el tratamiento del alcoholismo. También se describen las características farmacológicas de naltrexona y de nalmefeno y su utilidad en la práctica clínica. Resultados: Múltiples evidencias han demostrado la eficacia de naltrexona y nalmefeno para reducir el consumo de alcohol, tanto en animales de laboratorio como también en personas estudiadas en situación de bar experimental, aunque debido al diferente perfil receptorial, nalmefeno ha sido relacionado con una mayor eficacia para la reducción del consumo de alcohol, en ratas que presentan dependencia del alcohol. Además, un gran número de ensayos clínicos controlados han demostrado la eficacia de naltrexona para la prevención de recaídas, en personas que presentan un trastorno por dependencia del alcohol. Ensayos clínicos controlados recientes han demostrado la eficacia de nalmefeno “a demanda” para reducir el consumo de alcohol, en personas que presentan un trastorno por dependencia del alcohol de baja gravedad. Conclusiones: Tanto naltrexona como nalmefeno han demostrado ser fármacos seguros, bien tolerados, de manejo sencillo, y eficaces para el tratamiento del trastorno por dependencia del alcohol, (actualmente llamado trastorno por consumo de alcohol). A partir de recientes ensayos clínicos controlados se ha comprobado que nalmefeno produce una reducción significativa del consumo de alcohol, lo cual supone un nuevo objetivo que amplía las posibilidades de

  14. Discovery of a Novel Series of Orally Bioavailable and CNS Penetrant Glucagon-like Peptide-1 Receptor (GLP-1R) Noncompetitive Antagonists Based on a 1,3-Disubstituted-7-aryl-5,5-bis(trifluoromethyl)-5,8-dihydropyrimido[4,5-d]pyrimidine-2,4(1H,3H)-dione Core.

    Science.gov (United States)

    Nance, Kellie D; Days, Emily L; Weaver, C David; Coldren, Anastasia; Farmer, Tiffany D; Cho, Hyekyung P; Niswender, Colleen M; Blobaum, Anna L; Niswender, Kevin D; Lindsley, Craig W

    2017-02-23

    A duplexed, functional multiaddition high throughput screen and subsequent optimization effort identified the first orally bioavailable and CNS penetrant glucagon-like peptide-1 receptor (GLP-1R) noncompetitive antagonist. Antagonist 5d not only blocked exendin-4-stimulated insulin release in islets but also lowered insulin levels while increasing blood glucose in vivo.

  15. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.

    2009-01-01

    period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...... a maximal oxygen uptake ((V) over dotO(2max)) test and a prolonged exercise test, consisting of 60 min of submaximal cycling followed by exercise to fatigue at 90% of (V) over dotO(2max). Main Outcome Measures: (V) over dotO(2max) was measured before and after the treatment period. Hormonal and metabolic......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...

  16. Ability of ketanserin to block different receptors in human placental vessels.

    Science.gov (United States)

    Marin, J; Reviriego, J; Fernandez-Alfonso, M S

    1990-03-01

    5-Hydroxytryptamine (5-HT), noradrenaline (NA) and histamine induced concentration-dependent contractions in segments of human chorionic arteries and veins, whereas clonidine, an alpha 2-adrenoceptor agonist, had no effect. 5-HT and histamine induced strong contractions, while NA elicited weak contractions in some segments. The maximal response was similar for 5-HT and histamine. The order of potency (EC50 values) was: 5-HT greater than or equal to NA greater than or equal to histamine. These agonists induced tachyphylaxis, and single concentrations caused transient contractions. Contractions elicited by 5-HT were antagonized by ketanserin, a 5-HT2-receptor antagonist, which also antagonized the responses to NA and histamine, but at greater concentrations than those needed for 5-HT responses. Contractions elicited by histamine were reduced by diphenydramine. Low concentrations of 5-HT amplified contractions caused by NA and histamine. The results indicate that: (i) 5-HT is the most potent constrictor agent tested in these vessels; (ii) its effects are mediated by 5-HT2-receptors; and (iii) ketanserin at therapeutic plasma concentrations (10(-7) M) seems to block mainly 5-HT2-receptors, and alpha 1-adrenergic- and H1-receptors to a small extent only.

  17. Effects of Proton Pump Inhibitors and H2 Receptor Antagonists on the Ileum Motility

    Directory of Open Access Journals (Sweden)

    Atilla Kurt

    2011-01-01

    Full Text Available Objectives. To investigate the effects of proton pump inhibitors (PPIs and H2 receptor antagonists on ileum motility in rats with peritonitis and compare changes with control group rats. Methods. Peritonitis was induced by cecal ligation and puncture in 8 rats. Another of 8 rats underwent a sham operation and were accepted as controls. Twenty-four hours later after the operation, the rats were killed, and their ileum smooth muscle was excised and placed in circular muscle direction in a 10 mL organ bath. Changes in amplitude and frequency of contractions were analyzed before and after PPIs and H2 receptor blockers. Results. PPI agents decreased the motility in a dose-dependent manner in ileum in both control and intraabdominal sepsis groups. While famotidine had no significant effect on ileum motility, ranitidine and nizatidine enhanced motility in ileum in both control and intraabdominal sepsis groups. This excitatory effect of H2 receptor antagonists and inhibitor effects of PPIs were significantly high in control group when compared to the peritonitis group. The inhibitor effect of pantoprazole on ileum motility was significantly higher than the other two PPI agents. Conclusions. It was concluded that H2 receptor antagonists may be more effective than PPIs for recovering the bowel motility in the intraabdominal sepsis situation.

  18. Pharmacology of JB-9315, a new selective histamine H2-receptor antagonist.

    Science.gov (United States)

    Palacios, B; Montero, M J; Sevilla, M A; San Román, L

    1998-02-01

    1. The histamine H2-receptor antagonistic activity and antisecretory and antiulcer effects of JB-9315 were studied in comparison with the standard H2 blocker ranitidine. 2. In vitro, JB-9315 is a competitive antagonist of histamine H2 receptors in the isolated, spontaneously beating guinea-pig right atrium, with a pA2 value of 7.30 relative to a value of 7.36 for ranitidine. JB-9315 was specific for the histamine H2 receptor because, at high concentration, it did not affect histamine- or acetylcholine-induced contractions in guinea-pig isolated ileum or rat isolated duodenum, respectively. 3. JB-9315 dose dependently inhibited histamine-, pentagastrin- or carbachol-stimulated acid secretion and basal secretion in the perfused stomach preparation of the anesthetized rat. In the pylorus-ligated rat after intraperitoneal administration, total acid output over 4 h was inhibited by JB-9315 with an ID50 of 32.8 mg/kg, confirming its H2-receptor antagonist properties. 4. JB-9315 showed antiulcer activity against cold stress plus indomethacin-induced lesions with an ID50 of 6.8 mg/kg. 5. JB-9315, 50 and 100 mg/kg, inhibited macroscopic gastric hemorrhagic lesions induced by ethanol. In contrast, ranitidine (50 mg/kg) failed to reduce these lesions. 6. These results indicate that JB-9315 is a new antiulcer drug that exerts a cytoprotective effect in addition to its gastric antisecretory activity.

  19. The 5-HT2A receptor antagonist M100907 produces antiparkinsonian effects and decreases striatal glutamate

    Directory of Open Access Journals (Sweden)

    Twum eAnsah

    2011-06-01

    Full Text Available 5-HT plays a regulatory role in voluntary movements of the basal ganglia and have a major impact on disorders of the basal ganglia such as Parkinson’s disease (PD. Clinical studies have suggested that 5-HT2 receptor antagonists may be useful in the treatment of the motor symptoms of PD. We hypothesized that 5-HT2A receptor antagonists may restore motor function by regulating glutamatergic activity in the striatum. Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP exhibited decreased performance on the beam-walking apparatus. Peripheral administration of the 5-HT2A receptor antagonist M100907 improved performance of MPTP-treated mice on the beam-walking apparatus. In vivo microdialysis revealed an increase in striatal extracellular glutamate in MPTP-treated mice and local perfusion of M100907 into the dorsal striatum significantly decreased extracellular glutamate levels in saline and MPTP-treated mice. Our studies suggest that blockade of 5-HT2A receptors may represent a novel therapeutic target for the motor symptoms of Parkinson’s disease.

  20. Classification of 5-HT1A receptor agonists and antagonists using GA-SVM method

    Institute of Scientific and Technical Information of China (English)

    Xue-lian ZHU; Hai-yan CAI; Zhi-jian XU; Yong WANG; He-yao WANG; Ao ZHANG; Wei-liang ZHU

    2011-01-01

    Aim:To construct a reliable computational model for the classification of agonists and antagonists of 5-HT1A receptor.Methods:Support vector machine (SVM),a well-known machine learning method,was employed to build a prediction model,and genetic algorithm (GA) was used to select the most relevant descriptors and to optimize two important parameters,C and r of the SVM model.The overall dataset used in this study comprised 284 ligands of the 5-HT1A receptor with diverse structures reported in the literatures.Results:A SVM model was successfully developed that could be used to predict the probability of a ligand being an agonist or antagonist of the 5-HT1A receptor.The predictive accuracy for training and test sets was 0.942 and 0.865,respectively.For compounds with probability estimate higher than 0.7,the predictive accuracy of the model for training and test sets was 0.954 and 0.927,respectively.To further validate our model,the receiver operating characteristic (ROC) curve was plotted,and the Area-Under-the-ROC-Curve (AUC) value was calculated to be 0.883 for training set and 0.906 for test set.Conclusion:A reliable SVM model was successfully developed that could effectively distinguish agonists and antagonists among the ligands of the 5-HT1A receptor.To our knowledge,this is the first effort for the classification of 5-HT1A receptor agonists and antagonists based on a diverse dataset.This method may be used to classify the ligands of other members of the GPCR family.

  1. Opioid receptor antagonists increase [Ca2+]i in rat arterial smooth muscle cells in hemorrhagic shock

    Institute of Scientific and Technical Information of China (English)

    Li KAI; Zhong-feng WANG; Yu-liang SHI; Liang-ming LIU; De-yao HU

    2004-01-01

    AIM: To examine the effects of opioid receptor antagonists and norepinephrine on intracellular free Ca2+ concentration ([Ca2+]i) in mesenteric arterial (MA) smooth muscle cells (SMC) isolated from normal and hemorrhagic shocked rats in the vascular hyporesponse stage. METHODS: The rat model of hemorrhagic shock was made by withdrawing blood to decrease the artery mean blood pressure to 3.73-4.26 kPa and keeping at the level for 3 h.[Ca2+]i of vascular smooth muscle cells (VSMC) were detected by the laser scan confocal microscopy. RESULTS:In the hyporesponse VMSC of rats in hemorrhagic shock, selective δ-, κ-, and μ-opioid receptor antagonists (naltrindole, nor-binaltorphimine, and β-funaltrexamine, 100 nmol/L) as well as norepinephrine 5 μmol/L significantly increased [Ca2+]i by 47 %±13 %, 37 %±14 %, 33 %±10 %, and 54 %±17 %, respectively, although their effects were lower than those in the normal rat cells (the increased values were 148 %±54 %, 130 %±44 %, 63 %±17 %and 110 %±38 %, respectively); and the norepinephrine-induced increase in [Ca2+]i was further augmented by three δ-, κ-, and μ-opioid receptor antagonists (50 nmol/L, respectively) application (from 52 %± 16 % to 99 %±29 %,146 %±54 % and 137 %±47 %, respectively). CONCLUSION: The disorder of [Ca2+]i regulation induced by hemorrhagic shock was mediated by opioid receptor and α-adrenoceptor, which may be partly responsible for the vascular hyporesponse, and the opioid receptor antagonists improved the response of resistance arteries to vascular stimulants in decompensatory stage of hemorrhagic shock.

  2. Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist.

    Science.gov (United States)

    Papp, Marius; Gruca, Piotr; Willner, Paul

    2002-11-01

    ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some

  3. The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol.

    Directory of Open Access Journals (Sweden)

    Pia Steensland

    Full Text Available BACKGROUND: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer 'liked' are still intensely 'wanted' [7], . The neurokinin 1 (NK1 receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974, in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. CONCLUSIONS/SIGNIFICANCE: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

  4. X-ray structures define human P2X3 receptor gating cycle and antagonist action

    Science.gov (United States)

    Mansoor, Steven E.; Lü, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric

    2016-10-01

    P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X3 receptor in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states. The open state structure harbours an intracellular motif we term the ‘cytoplasmic cap’, which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.

  5. A rational approach to the design and synthesis of a new bradykinin B(1) receptor antagonist.

    Science.gov (United States)

    Bedos, P; Amblard, M; Subra, G; Dodey, P; Luccarini, J M; Paquet, J L; Pruneau, D; Aumelas, A; Martinez, J

    2000-06-15

    We have previously synthesized a potent and selective B(1) bradykinin receptor antagonist, JMV1645 (H-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-BT-OH), containing a dipeptide mimetic ((3S)-amino-5-carbonylmethyl-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety) at the C-terminal. Analogues of this potent B(1) bradykinin receptor antagonist in which the central Pro(2)-Hyp(3)-Gly(4)-Igl(5) tetrapeptide has been replaced by constrained N-1-substituted-1,3,8-triazaspiro¿4. 5decan-4-one ring system were synthesized. Among these analogues, compound JMV1640 (1) was found to have an affinity of 24.10 +/- 9.48 nM for the human cloned B(1) receptor. It antagonized the ¿des-Arg(10)-kallidin-induced contraction of the human umbilical vein (pA(2) = 6.1 +/- 0.1). Compound 1 was devoid of agonist activity at the kinin B(1) receptor. Moreover, it did not bind to the human cloned B(2) receptor. Therefore, JMV1640 constitutes a lead compound for the rational search of nonpeptide B(1) receptor analogues based on the BK sequence.

  6. Gold nanoparticle–choline complexes can block nicotinic acetylcholine receptors

    Directory of Open Access Journals (Sweden)

    Chur Chin

    2010-04-01

    Full Text Available Chur Chin1, In Kyeom Kim2, Dong Yoon Lim3, Ki Suk Kim4, Hyang Ae Lee4, Eun Joo Kim41Department of Pediatrics, Fatima Hospital, Daegu, Korea; 2Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu, Korea; 3Department of Pharmacology, School of Medicine, Chosun University, Gwangju, Korea; 4Korea Institute of Toxicology, Daejeon, KoreaAbstract: We identified a novel class of direct ion-channel blockers of ligand-gated ion channels called the gold nanoparticle–choline complex. Negatively charged gold nanoparticles (1.4 nm block ion pores by binding to the sulfur group of the cysteine loop of nicotinic acetylcholine receptors (nAChRs, and currents evoked by acetylcholine (Ach can break these bonds. The current evoked by ACh in nAChRs was blocked directly in ion pores by the gold nanoparticle–choline complex. In adrenal-gland perfusion studies, the complex also blocked nAChRs by diminishing catecholamine release by about 75%. An in vivo study showed muscle relaxation in rats after injection of the complex. These results will foster the application of gold nanoparticles as a direct ion-channel blocker. Keywords: negatively charged gold nanoparticle, choline, gold–sulfur bond, nicotinic acetylcholine receptor, direct ion-channel blocker

  7. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes

    Science.gov (United States)

    Villalobos, Claudio A; Bull, Paulina; Sáez, Patricio; Cassels, Bruce K; Huidobro-Toro, J Pablo

    2004-01-01

    We recently described that several 2-(2,5-dimethoxy-4-substituted phenyl)ethylamines (PEAs), including 4-I=2C-I, 4-Br=2C-B, and 4-CH3=2C-D analogs, are partial agonists at 5-HT2C receptors, and show low or even negligible intrinsic efficacy at 5-HT2A receptors. These results raised the proposal that these drugs may act as 5-HT2 antagonists. To test this hypothesis, Xenopus laevis oocytes were microinjected with the rat clones for 5-HT2A or 5-HT2C receptors. The above-mentioned PEAs and its 4-H analog (2C-H) blocked the 5-HT-induced currents at 5-HT2A, but not at the 5-HT2C receptor, revealing 5-HT2 receptor subtype selectivity. The 5-HT2A receptor antagonism required a 2-min preincubation to attain maximum inhibition. All PEAs tested shifted the 5-HT concentration–response curves to the right and downward. Their potencies varied with the nature of the C(4) substituent; the relative rank order of their 5-HT2A receptor antagonist potency was 2C-I>2C-B>2C-D>2C-H. The present results demonstrate that in X. laevis oocytes, a series of 2,5-dimethoxy-4-substituted PEAs blocked the 5-HT2A but not the 5-HT2C receptor-mediated responses. As an alternative hypothesis, we suggest that the psychostimulant activity of the PEAs may not be exclusively associated with partial or full 5-HT2A receptor agonism. PMID:15006903

  8. [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.

    Science.gov (United States)

    Marczak, Ewa D; Jinsmaa, Yunden; Li, Tingyou; Bryant, Sharon D; Tsuda, Yuko; Okada, Yoshio; Lazarus, Lawrence H

    2007-10-01

    [N-allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective micro-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[35S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-allyl-Dmt1]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.

  9. A long-acting GH receptor antagonist through fusion to GH binding protein.

    Science.gov (United States)

    Wilkinson, Ian R; Pradhananga, Sarbendra L; Speak, Rowena; Artymiuk, Peter J; Sayers, Jon R; Ross, Richard J

    2016-10-12

    Acromegaly is a human disease of growth hormone (GH) excess with considerable morbidity and increased mortality. Somatostatin analogues are first line medical treatment but the disease remains uncontrolled in up to 40% of patients. GH receptor (GHR) antagonist therapy is more effective but requires frequent high-dose injections. We have developed an alternative technology for generating a long acting potent GHR antagonist through translational fusion of a mutated GH linked to GH binding protein and tested three candidate molecules. All molecules had the amino acid change (G120R), creating a competitive GHR antagonist and we tested the hypothesis that an amino acid change in the GH binding domain (W104A) would increase biological activity. All were antagonists in bioassays. In rats all antagonists had terminal half-lives >20 hours. After subcutaneous administration in rabbits one variant displayed a terminal half-life of 40.5 hours. A single subcutaneous injection of the same variant in rabbits resulted in a 14% fall in IGF-I over 7 days.

  10. Synthesis of [{sup 18}F]-labelled nebivolol as a β{sub 1}-adrenergic receptor antagonist for PET imaging agent

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Taek Soo; Park, Jeong Hoon; Lee, Jun Young; Yang, Seung Dae [Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute (KAERI), Jeongeup (Korea, Republic of); Chang, Dong Jo [College of pharmacy, Sunchon National University, Suncheon (Korea, Republic of)

    2017-02-15

    Selective β{sub 1}-agonist and antagonists are used for the treatment of cardiac diseases including congestive heart failure, angina pectoris and arrhythmia. Selective β{sub 1}-antagonists including nebivolol have high binding affinity on β{sub 1}-adrenergic receptor, not β{sub 2}-receptor mainly expressed in smooth muscle. Nebivolol is one of most selective β{sub 1}-blockers in clinically used β{sub 1}- blockers including atenolol and bisoprolol. We tried to develop clinically useful cardiac PET tracers using a selective β{sub 1}-blocker. Nebivolol is C{sub 2}-symmetric and has two chromane moiety with a secondary amino alcohol and aromatic fluorine. We adopted the general synthetic strategy using epoxide ring opening reaction. Unlike formal synthesis of nebivolol, we prepared two chromane building blocks with fluorine and iodine which was transformed to diaryliodonium salt for labelling of {sup 18}F. Two epoxide building blocks were readily prepared from commercially available chromene carboxylic acids (1, 8). Then, the amino alcohol building block (15) was prepared by ammonolysis of epoxide (14) followed by coupling reaction with the other building block, epoxide (7). Diaryliodonium salt, a precursor for {sup 18}F-aromatic substitution, was synthesized in moderate yield which was readily subjected to {sup 18}F-aromatic substitution to give {sup 18}F-labelled nebivolol.

  11. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists.

    Science.gov (United States)

    Greineisen, William E; Turner, Helen

    2010-05-01

    The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered.

  12. ANALYSIS OF INTERLEUKIN-1 RECEPTOR ANTAGONIST GENE POLYMORPHISM IN CHINESE PATIENTS WITH ALZHEIMER'S DISEASE

    Institute of Scientific and Technical Information of China (English)

    Sheng Bi; De-sheng Wang; Guo-lin Li; Shang-ha Pan

    2004-01-01

    Objective To identify an interaction between the interleukin-1 receptor antagonist gene polymorphism and risk of Alzheimer's disease.Methods The study included 117 healthy controls, 85 patients with Alzheimer's disease in a Northeastern Chinese population of Han nationality. Genotypes were determined by a polymerase chain reaction amplification of the intron 2 fragment,harbouring a variable number of short tandem nucleotide sequences. Amplification products were separated on a 2% agarose gel.Results The allele 2 frequency was 27% in healthy controls, and 21% in patients with Alzheimer's disease. Thus for allele 2 as well as for all other alleles, genotypes, or carriage rates, no significant differences compared with controls.Conclusions No association ofinterleukin-1 receptor antagonist gene polymorphism with Alzheimer's disease was identified in this population. It is also possible that the increased risk and disease modifying effects are caused by linkage disequilibrium with other genomic variants in other nearby genes.

  13. The safety of interleukin-1 receptor antagonist (anakinra in the treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    L. Riente

    2011-09-01

    Full Text Available The safety profile of interleukin-1 receptor antagonist (anakinra has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71% and headache (13.6%. No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis.

  14. Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

    Institute of Scientific and Technical Information of China (English)

    Wei CHEN; Cheng XU; Hong-ying LIU; Long LONG; Wei ZHANG; Zhi-bing ZHENG; Yun-de XIE; Li-li WANG; Song LI

    2011-01-01

    To characterize the biological profiles of M J08,a novel selective CB1 receptor antagonist.Methods:Radioligand binding assays were performed using rat brain and spleen membrane preparations.CB1 and CB2 receptor redistribution and intracellular Ca2+ ([Ca2+]1) assays were performed with IN CELL Analyzer.Inverse agonism was studied using intracellular cAMP assays,and in guinea-pig ileum and mouse vas deferens smooth muscle preparations.In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice.Results:In radioligand binding assay,M J08 selectively antagonized CB1 receptor (IC50=99.9 nmol/L).In EGFP-CB1_U20S cells,its IC50 value against CB1 receptor activation was 30.23 nmol/L (SR141716A:32.16 nmol/L).WIN 55,212-2 (1 μmol/L) increased [Ca2+]1 in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB1 cells.M J08 (10 nmol/L-1O μmol/L)blocked both the WIN 55,212-2-induced effects.Furthermore,M J08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA2=10.29±1.05).M J08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle.M J08 significantly increased the cAMP level in CHO-hCB1 cells with an EC50 value of 78.6 nmol/L,which was lower than the EC50 value for SR141716A (159.2 nmol/L).Besides the more potent pharmacological effects of cannabinoid CB1 receptor antagonism in DIO mice,such as reducing food intake,decreasing body weight,and ameliorating dyslipidemia,M J08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo.Conclusion:M J08 is a novel,potent and selective CB1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB1 receptors.

  15. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin AT1 receptors antagonists.

    Science.gov (United States)

    Pernomian, Larissa; Pernomian, Laena; Gomes, Mayara S; da Silva, Carlos H T P

    2015-12-15

    The interplay between angiotensin AT1 receptors and MAS receptors relies on several inward regulatory mechanisms from renin-angiotensin system (RAS) including the functional crosstalk between angiotensin II and angiotensin-(1-7), the competitive AT1 antagonism exhibited by angiotensin-(1-7), the antagonist feature assigned to AT1/MAS heterodimerization on AT1 signaling and the AT1-mediated downregulation of angiotensin-converting enzyme 2 (ACE2). Recently, such interplay has acquired an important significance to RAS Pharmacology since a few studies have supporting strong evidences that MAS receptors mediate the effects elicited by AT1 antagonists. The present Perspective provides an overview of the regulatory mechanisms involving AT1 and MAS receptors, their significance to RAS Pharmacology and the future directions on the interplay between angiotensin receptors. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Effects of dopamine receptor agonist and antagonists on cholestasis-induced anxiolytic-like behaviors in rats.

    Science.gov (United States)

    Reza Zarrindast, Mohammad; Eslimi Esfahani, Delaram; Oryan, Shahrbano; Nasehi, Mohammad; Torabi Nami, Mohammad

    2013-02-28

    Dysfunctions in the dopamine transmission system have been suggested to contribute to the pathogenesis of hepatic encephalopathy. In an experimental animal model, cholestasis induction through bile duct ligation may present several main pathological features of hepatic encephalopathy. Dopaminergic systems are shown to play pivotal roles in regulation of anxiety-like behaviors. The main bile duct in male Wistar rats, weighing 220-240 g, was ligated using two ligatures plus duct transection in between. Anxiety-like behaviors were measured using the elevated plus maze task. Cholestasis increased the open arm time percentage (%OAT), 13 but not 10 days after bile duct ligation, indicating an anxiolytic-like effect. Sole intraperitoneal injection of apomorphine (dopamine D1/D2 receptor agonist, 0.25 mg/kg), SCH23390 (dopamine D1 receptor antagonist, 0.005, 0.01 and 0.02 mg/kg) or sulpiride (dopamine D2 receptor antagonist, 0.125, 0.25 and 0.5 mg/kg) did not alter %OAT, open arm entries percentage (%OAE) and locomotor activity in the sham-operated rats. Meanwhile, the higher dose apomorphine (0.5 mg/kg) induced anxiolytic-like behaviors in this group. The subthreshold dose injection of SCH23390 or sulpiride, partially reversed the anxiolytic-like behaviors induced by cholestasis (13 days after bile duct ligation). On the other hand, subthreshold dose of apomorphine in cholestatic rats (10 days post bile duct ligation) induced anxiolytic-like effects which could be blocked by SCH23390 or sulpiride. The effective doses of above drugs did not alter locomotor activity, number of rearings, groomings and defections. These findings suggested that the dopaminergic system may potentially be involved in the modulation of cholestasis-induced anxiolytic-like behaviors in rats.

  17. How microelectrode array-based chick forebrain neuron biosensors respond to glutamate NMDA receptor antagonist AP5 and GABAA receptor antagonist musimol

    Directory of Open Access Journals (Sweden)

    Serena Y. Kuang

    2016-09-01

    Full Text Available We have established a long-term, stable primary chick forebrain neuron (FBN culture on a microelectrode array platform as a biosensor system for neurotoxicant screening and for neuroelectrophysiological studies for multiple purposes. This paper reports some of our results, which characterize the biosensor pharmacologically. Dose-response experiments were conducted using NMDA receptor antagonist AP5 and GABAA receptor agonist musimol (MUS. The chick FBN biosensor (C-FBN-biosensor responds to the two agents in a pattern similar to that of rodent counterparts; the estimated EC50s (the effective concentration that causes 50% inhibition of the maximal effect are 2.3 μM and 0.25 μM, respectively. Intercultural and intracultural reproducibility and long-term reusability of the C-FBN-biosensor are addressed and discussed. A phenomenon of sensitization of the biosensor that accompanies intracultural reproducibility in paired dose-response experiments for the same agent (AP5 or MUS is reported. The potential application of the C-FBN-biosensor as an alternative to rodent biosensors in shared sensing domains (NMDA receptor and GABAA receptor is suggested.

  18. Relaxant effect of the H2-receptor antagonist oxmetidine on guinea-pig and human airways.

    OpenAIRE

    Advenier, C; Gnassounou, J. P.; Scarpignato, C.

    1987-01-01

    The effects of three different H2-receptor antagonists (cimetidine, ranitidine and oxmetidine) were tested on isolated preparations of guinea-pig trachea and human bronchus against contractions induced by acetylcholine, histamine and potassium chloride (KCl). In addition, their influence on calcium concentration-response curves in guinea-pig tracheal spirals was examined in a potassium-rich solution (30 mM). Finally, their effects were studied in vivo against acetylcholine and histamine-induc...

  19. A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

    Science.gov (United States)

    Filipski, Kevin J; Bian, Jianwei; Ebner, David C; Lee, Esther C Y; Li, Jian-Cheng; Sammons, Matthew F; Wright, Stephen W; Stevens, Benjamin D; Didiuk, Mary T; Tu, Meihua; Perreault, Christian; Brown, Janice; Atkinson, Karen; Tan, Beijing; Salatto, Christopher T; Litchfield, John; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2012-01-01

    A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.

  20. An Autoinflammatory Disease with Deficiency of the Interleukin-1–Receptor Antagonist

    Science.gov (United States)

    Aksentijevich, Ivona; Masters, Seth L.; Ferguson, Polly J.; Dancey, Paul; Frenkel, Joost; van Royen-Kerkhoff, Annet; Laxer, Ron; Tedgård, Ulf; Cowen, Edward W.; Pham, Tuyet-Hang; Booty, Matthew; Estes, Jacob D.; Sandler, Netanya G.; Plass, Nicole; Stone, Deborah L.; Turner, Maria L.; Hill, Suvimol; Butman, John A.; Schneider, Rayfel; Babyn, Paul; El-Shanti, Hatem I.; Pope, Elena; Barron, Karyl; Bing, Xinyu; Laurence, Arian; Lee, Chyi-Chia R.; Chapelle, Dawn; Clarke, Gillian I.; Ohson, Kamal; Nicholson, Marc; Gadina, Massimo; Yang, Barbara; Korman, Benjamin D.; Gregersen, Peter K.; van Hagen, P. Martin; Hak, A. Elisabeth; Huizing, Marjan; Rahman, Proton; Douek, Daniel C.; Remmers, Elaine F.; Kastner, Daniel L.; Goldbach-Mansky, Raphaela

    2010-01-01

    Background Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone. Methods We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN. Results We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1β stimulation. Patients treated with anakinra responded rapidly. Conclusions We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.) PMID:19494218

  1. Efficient photoaffinity labeling of the rat V1a vasopressin receptor using a linear azidopeptidic antagonist.

    Science.gov (United States)

    Carnazzi, E; Aumelas, A; Phalipou, S; Mouillac, B; Guillon, G; Barberis, C; Seyer, R

    1997-08-01

    We have synthesized and fully characterized by fast-atom-bombardment-mass, NMR and ultraviolet spectroscopies the vasopressin antagonist 3-azidophenylpropionyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr(3I )-NH2. Easily radioiodinatable just before use, it has a high affinity for the natural rat liver V1a receptor [dissociation constant (Kd) = 54 +/- 20 pM; Carnazzi, E., Aumelas, A., Barberis, C., Guillon, G. & Seyer, R. (1994) J. Med. Chem. 37, 1841-1849] and for both the rat vasopressin V1a receptor expressed in Spodoptera frugiperda 9 cells (Sf9 cells, Kd = 688 +/- 35 pM) and in COS-7 cells (Kd = 320 +/- 20 pM). This probe labels specifically the V1a receptors in an ultraviolet-dependent manner, and binds covalently to about 12% of the receptors with high stability over several days, even in dissociation or solubilization conditions. SDS/PAGE studies and autoradiographic analyses of the photolabeled receptors reveal a single band (49.5 kDa) and two bands (63 kDa and 93.6 kDa) for receptor-probe associations obtained in Sf9 and COS-7 cells respectively. These molecular masses are consistent with non-glycosylated and highly glycosylated forms of the receptor, according to each expression system. In rat liver membranes, we have identified apparent molecular masses of about 32, 45 and more than 67 kDa. We finally demonstrated a proteolysis of the receptor that appeared to be Zn2+ and leupeptin sensitive. The high potency of this ligand is promising for the monitoring of the purification of the V1a receptor and for mapping its antagonist-binding site.

  2. Extended N-Arylsulfonylindoles as 5-HT₆ Receptor Antagonists: Design, Synthesis & Biological Evaluation.

    Science.gov (United States)

    Vera, Gonzalo; Lagos, Carlos F; Almendras, Sebastián; Hebel, Dan; Flores, Francisco; Valle-Corvalán, Gissella; Pessoa-Mahana, C David; Mella-Raipán, Jaime; Montecinos, Rodrigo; Recabarren-Gajardo, Gonzalo

    2016-08-16

    Based on a known pharmacophore model for 5-HT₆ receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT₆ receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT₆ receptor functional assays. Compounds 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol (4b), 1-(1-(4-iodophenylsulfonyl)-1H-indol-3-yl)-2-(4-(2-methoxyphenyl)piperazin-1-yl)ethanol (4g) and 2-(4-(2-methoxyphenyl)piperazin-1-yl)-1-(1-(naphthalen-1-ylsulfonyl)-1H-indol-3-yl)ethanol (4j) showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83). Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM) in calcium mobilisation functional assay.

  3. Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation

    Directory of Open Access Journals (Sweden)

    Gonzalo Vera

    2016-08-01

    Full Text Available Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenylpiperazin-1-yl-1-(1-tosyl-1H-indol-3-ylethanol (4b, 1-(1-(4-iodophenylsulfonyl-1H-indol-3-yl-2-(4-(2-methoxyphenylpiperazin-1-ylethanol (4g and 2-(4-(2-methoxyphenylpiperazin-1-yl-1-(1-(naphthalen-1-ylsulfonyl-1H-indol-3-ylethanol (4j showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83. Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM in calcium mobilisation functional assay.

  4. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists.

    Science.gov (United States)

    Altun, Ahmet; Yildirim, Kemal; Ozdemir, Ercan; Bagcivan, Ihsan; Gursoy, Sinan; Durmus, Nedim

    2015-09-01

    Cannabinoid CB1 and CB2 receptor antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance. The aim of this study was to investigate the effects of AM251 (a selective CB1 antagonist) and JTE907 (a selective CB2 antagonist) on morphine analgesia and tolerance in rats. Adult male Wistar albino rats weighing 205-225 g were used in these experiments. To constitute morphine tolerance, we used a 3 day cumulative dosing regimen. After the last dose of morphine was injected on day 4, morphine tolerance was evaluated by analgesia tests. The analgesic effects of morphine (5 mg/kg), ACEA (a CB1 receptor agonist, 5 mg/kg), JWH-015 (a CB2 receptor agonist, 5 mg/kg), AM251 (1 mg/kg) and JTE907 (5 mg/kg) were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot-plate analgesia tests. Our findings indicate that ACEA and JWH907 significantly increased morphine analgesia and morphine antinociceptive tolerance in the analgesia tests. In contrast, the data suggested that AM251 and JTE907 significantly attenuated the expression of morphine tolerance. In conclusion, we observed that co-injection of AM251 and JTE907 with morphine attenuated expression of tolerance to morphine analgesic effects and decreased the morphine analgesia.

  5. Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor.

    Science.gov (United States)

    Burch, Jason D; Farand, Julie; Colucci, John; Sturino, Claudio; Ducharme, Yves; Friesen, Richard W; Lévesque, Jean-François; Gagné, Sébastien; Wrona, Mark; Therien, Alex G; Mathieu, Marie-Claude; Denis, Danielle; Vigneault, Erika; Xu, Daigen; Clark, Patsy; Rowland, Steve; Han, Yongxin

    2011-02-01

    Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.

  6. New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

    Science.gov (United States)

    Lupala, Cecylia S.; Gomez-Gutierrez, Patricia; Perez, Juan J.

    2016-01-01

    Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a receptor up-regulated during inflammation episodes or tissue trauma and B2 that is constitutively expressed in a variety of cell types. The goal of the present work is to carry out a structure-activity study of BK B2 antagonism, taking into account the stereochemical features of diverse non-peptide antagonists and the way these features translate into ligand anchoring points to complementary regions of the receptor, through the analysis of the respective ligand-receptor complex. For this purpose an atomistic model of the BK B2 receptor was built by homology modeling and subsequently refined embedded in a lipid bilayer by means of a 600 ns molecular dynamics trajectory. The average structure from the last hundred nanoseconds of the molecular dynamics trajectory was energy minimized and used as model of the receptor for docking studies. For this purpose, a set of compounds with antagonistic profile, covering maximal diversity were selected from the literature. Specifically, the set of compounds include Fasitibant, FR173657, Anatibant, WIN64338, Bradyzide, CHEMBL442294, and JSM10292. Molecules were docked into the BK B2 receptor model and the corresponding complexes analyzed to understand ligand-receptor interactions. The outcome of this study is summarized in a 3D pharmacophore that explains the observed structure-activity results and provides insight into the design of novel molecules with antagonistic profile. To prove the validity of the pharmacophore hypothesized a virtual screening process was also carried out. The pharmacophore was used as query to identify new hits using diverse databases of molecules. The results of this study revealed a set of new

  7. Examining SLV-323, a novel NK1 receptor antagonist, in a chronic psychosocial stress model for depression

    NARCIS (Netherlands)

    Czeh, B; Pudovkina, O; van der Hart, MGC; Simon, M; Heilbronner, U; Michaelis, T; Watanabe, T; Frahm, J; Fuchs, E

    2005-01-01

    Rationale: Substance P antagonists have been proposed as candidates for a new class of antidepressant compounds. Objectives: We examined the effects of SLV-323, a novel neurokinin 1 receptor (NK1R) antagonist, in the chronic psychosocial stress paradigm of adult male tree shrews. Methods: Animals we

  8. Effects of iodoproxyfan, a potent and selective histamine H3 receptor antagonist, on alpha 2 and 5-HT3 receptors.

    Science.gov (United States)

    Schlicker, E; Pertz, H; Bitschnau, H; Purand, K; Kathmann, M; Elz, S; Schunack, W

    1995-07-01

    We determined the affinity and/or potency of the novel H3 receptor antagonist iodoproxyfan at alpha 2 and 5-HT3 receptors. Iodoproxyfan and rauwolscine (a reference alpha 2 ligand) (i) monophasically displaced 3H-rauwolscine binding to rat brain cortex membranes (pKi 6.79 and 8.59); (ii) facilitated the electrically evoked tritium overflow from superfused mouse brain cortex slices preincubated with 3H-noradrenaline (pEC50 6.46 and 7.91) and (iii) produced rightward shifts of the concentration-response curve (CRC) of (unlabelled) noradrenaline for its inhibitory effect on the evoked overflow (pA2 6.65 and 7.88). In the guinea-pig ileum, iodoproxyfan 6.3 mumol/l failed to evoke a contraction by itself but depressed the maximum of the CRC of 5-hydroxytryptamine (pD'2 5.24). Tropisetron (a reference 5-HT3 antagonist) produced rightward shifts of the CRC of 5-hydroxytryptamine (pA2 7.84). In conclusion, the affinity/potency of iodoproxyfan at H3 receptors (range 8.3-9.7 [1]) exceeds that at alpha 2 receptors by at least 1.5 log units and that at 5-HT3 receptors by at least 3 log units.

  9. Possible Mechanisms for Functional Antagonistic Effect of Ferula assafoetida on Muscarinic Receptors in Tracheal Smooth Muscle

    Science.gov (United States)

    Kiyanmehr, Majid; Boskabady, Mohammad Hossein; Khazdair, Mohammad Reza; Hashemzehi, Milad

    2016-01-01

    Background The contribution of histamine (H1) receptors inhibitory and/or β-adrenoceptors stimulatory mechanisms in the relaxant property of Ferula assa-foetida. (F. asafoetida) was examined in the present study. Methods We evaluated the effect of three concentrations of F. asafoetida extract (2.5, 5, and 10 mg/mL), a muscarinic receptors antagonist, and saline on methacholine concentration-response curve in tracheal smooth muscles incubated with β-adrenergic and histamine (H1) (group 1), and only β-adrenergic (group 2) receptors antagonists. Results EC50 values in the presence of atropine, extract (5 and 10 mg/mL) and maximum responses to methacholine due to the 10 mg/mL extract in both groups and 5 mg/mL extract in group 1 were higher than saline (P < 0.0001, P = 0.0477, and P = 0.0008 in group 1 and P < 0.0001, P = 0.0438, and P = 0.0107 in group 2 for atropine, 5 and 10 mg/mL extract, respectively). Values of concentration ratio minus one (CR-1), in the presence of extracts were lower than atropine in both groups (P = 0.0339 for high extract concentration in group 1 and P < 0.0001 for other extract concentrations in both groups). Conclusion Histamine (H1) receptor blockade affects muscarinic receptors inhibitory property of F. asafoetida in tracheal smooth muscle PMID:27540324

  10. Different antagonist binding properties of rat pancreatic and cardiac muscarinic receptors

    Energy Technology Data Exchange (ETDEWEB)

    Waelbroeck, M.; Camus, J.; Winand, J.; Christophe, J.

    1987-11-09

    The antagonist binding properties of rat pancreatic and cardiac muscarinic receptors were compared. In both tissues pirenzepine (PZ) had a low affinity for muscarinic receptors labelled by (/sup 3/H)N-methylscopolamine ((/sup 3/)NMS) (K/sub D/ values of 140 and 280nM, respectively, in pancreatic and cardiac homogenates). The binding properties of pancreatic and cardiac receptors were, however, markedly different. This was indicated by different affinities for dicyclomine, (11-(/(2-((diethylamino)-methyl)-1-piperidinyl/acetyl)-5, 11-dihydro-6H-pyrido(2,3-b)(1,4) benzodiazepin-6-on)(AFDX-116), 4-diphenylacetoxy-N-methyl-piperidine methobromide (4-DAMP) and hexahydrosiladifenidol (HHSiD). Pancreatic and cardiac muscarinic receptros also showed different (/sup 3/H)NMS association and dissociation rates. These results support the concept of M2 receptor subtypes have different binding kinetic properties. 20 references, 3 figures, 1 table.

  11. Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists

    DEFF Research Database (Denmark)

    Mohsen, Amal M Y; Mandour, Yasmine M; Sarukhanyan, Edita

    2016-01-01

    A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch......-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site...... of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment...

  12. Early Use of the NMDA Receptor Antagonist Ketamine in Refractory and Superrefractory Status Epilepticus

    Directory of Open Access Journals (Sweden)

    F. A. Zeiler

    2015-01-01

    Full Text Available Refractory status epilepticus (RSE and superrefractory status epilepticus (SRSE pose a difficult clinical challenge. Multiple cerebral receptor and transporter changes occur with prolonged status epilepticus leading to pharmacoresistance patterns unfavorable for conventional antiepileptics. In particular, n-methyl-d-aspartate (NMDA receptor upregulation leads to glutamate mediated excitotoxicity. Targeting these NMDA receptors may provide a novel approach to otherwise refractory seizures. Ketamine has been utilized in RSE. Recent systematic review indicates 56.5% and 63.5% cessation in seizures in adults and pediatrics, respectively. No complications were described. We should consider earlier implementation of ketamine or other NMDA receptor antagonists, for RSE. Prospective study of early implementation of ketamine should shed light on the role of such medications in RSE.

  13. Dopamine receptors antagonistically regulate behavioral choice between conflicting alternatives in C. elegans.

    Directory of Open Access Journals (Sweden)

    Daoyong Wang

    Full Text Available Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+ by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop-2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through Gαo signaling pathway encoded by GOA-1 and EGL-10, and DOP-1 might act through Gαq signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the

  14. IL-1 receptor antagonist improves morphine and buprenorphine efficacy in a rat neuropathic pain model.

    Science.gov (United States)

    Pilat, Dominika; Rojewska, Ewelina; Jurga, Agnieszka M; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2015-10-05

    An interesting research and therapeutic problem is the reduced beneficial efficacy of opioids in the treatment of neuropathic pain. The present study sought to investigate the potential role of IL-1 family members in this phenomenon. We studied the time course of changes in IL-1alpha, IL-1beta, IL-1 receptor type I and IL-1 receptor antagonist mRNA and protein levels experienced by rats after chronic constriction injury (CCI) of the sciatic nerve using qRT-PCR and Western blot analysis. In CCI-exposed rats, spinal levels of IL-1alpha mRNA were slightly downregulated on the 7th day, and protein levels were not changed on the 7th and 14th days. Levels of IL-1 receptor antagonist and IL-1 receptor type I were slightly upregulated in the ipsilateral part of the spinal cord on the 7th and 14th days; however, protein levels were not changed at those time points. Interestingly, we observed that IL-1beta mRNA and protein levels were strongly elevated in the ipsilateral part of the dorsal spinal cord on the 7th and 14th days following CCI. Moreover, in rats exposed to a single intrathecal administration of an IL-1 receptor antagonist (100 ng i.t.) on the 7th and 14th day following CCI, symptoms of neuropathic pain were attenuated, and the analgesic effects of morphine (2.5 µg i.t.) and buprenorphine (2.5 µg i.t.) were enhanced. In summary, restoration of the analgesic activity of morphine and buprenorphine by blockade of IL-1 signaling suggests that increased IL-1beta responses may account for the decreased analgesic efficacy of opioids observed in the treatment of neuropathy.

  15. Effects of dopamine D1 and D2 receptor antagonists on laryngeal neurophysiology in the rat.

    Science.gov (United States)

    Feng, Xin; Henriquez, Victor M; Walters, Judith R; Ludlow, Christy L

    2009-08-01

    Hypophonia is an early symptom in Parkinson's disease (PD) that involves an increase in laryngeal muscle activity, interfering with voice production. Our aim was to use an animal model to better understand the role of different dopamine receptor subtypes in the control of laryngeal neurophysiology. First, we evaluated the combined effects of SCH23390-a D(1) receptor antagonist with a D(2) receptor antagonist (eticlopride) on laryngeal neurophysiology, and then tested the separate effects of selective receptor antagonists. Thyroarytenoid (TA) and gastrocnemius (GN) muscle activity was measured at rest and while stimulating the internal branch of superior laryngeal nerve to elicit the laryngeal adductor response (LAR) in alpha-chloralose-anesthetized rats. Paired stimuli at different interstimulus intervals between 250 and 5,000 ms measured central conditioning of the LAR. Changes in resting muscle activity, response latency, amplitude, and LAR conditioning after each drug were compared with the saline control. SCH23390 alone increased the resting TA muscle activity (P < 0.05). With the combined SCH23390 + eticlopride or SCH23390 alone, response latency decreased (P < 0.01), amplitude increased (P < 0.01), and the test LAR was reduced at 2,000-ms ISI (P < 0.01). No LAR changes occurred when eticlopride was administered alone at a low dose and only a tendency to suppress responses was found at a high dose. No changes in GN muscle activity occurred in any of the groups. The results suggest that a loss of stimulation of D(1) receptors plays a significant role in laryngeal pathophysiology in PD.

  16. Studies on the Antihypertensive Mechanism of adrenergic Receptor Antagonist Propranolol : Special Reference to the Role of Vasodilatory Prostaglandins

    OpenAIRE

    西宮, 孝敏; Perry V., Halushka

    1988-01-01

    β-adrenergic receptor antagonists are widely used to treat the patients with hypertension. The mechanism of the antihypertensive effect of these drugs was thought to be associated with 1) negative cardiac inotropic and chronotropic action, 2) suppression of renin secretion, and 3) effects on the central nervous system. However, the precise mechanism is still unknown. Long term therapy with β-adrenergic receptor antagonists is also associated with a reduction in the peripheral vascular resista...

  17. Behavioural interactions between 5-hydroxytryptophan, neuroleptic agents and 5-HT receptor antagonists in modifying rodent responding to aversive situations.

    OpenAIRE

    1995-01-01

    1. The ability of 5-hydroxytryptophan, 5-HT2 receptor antagonists and typical and atypical neuroleptic agents to modify behavioural responding to aversive situations was investigated in the mouse light/dark test and rat social interaction. 2. The administration of 5-hydroxytryptophan inhibited rat social interaction and the exploratory behaviour of mice in the light/dark test. 3. The 5-HT2 receptor antagonists, ketanserin, ritanserin, MDL11939, methysergide and RP62203, the neuroleptic agents...

  18. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    multifactorial, and likely due to disease, as well as the two study drugs enzalutamide and mifepristone . from There have been no dose limiting toxicities ...AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined

  19. [3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors.

    Science.gov (United States)

    Donnelly-Roberts, Diana L; Namovic, Marian T; Surber, Bruce; Vaidyanathan, Srirajan X; Perez-Medrano, Arturo; Wang, Ying; Carroll, William A; Jarvis, Michael F

    2009-01-01

    ATP-sensitive P2X7 receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1beta, and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Data from gene knockout studies and recently described selective antagonists indicate a role for P2X7 receptor activation in inflammation and pain. While several species selective P2X7 antagonists exist, A-804598 represents a structurally novel, competitive, and selective antagonist that has equivalent high affinity at rat (IC50 = 10 nM), mouse (IC50 = 9 nM) and human (IC50 = 11 nM) P2X7 receptors. A-804598 also potently blocked agonist stimulated release of IL-1beta and Yo-Pro uptake from differentiated THP-1 cells that natively express human P2X7 receptors. A-804598 was tritiated ([3H]A-804598; 8.1Ci/mmol) and utilized to study recombinant rat P2X7 receptors expressed in 1321N1 cells. [3H]A-804598 labeled a single class of high affinity binding sites (Kd=2.4 nM and apparent Bmax=0.56 pmol/mg). No specific binding was observed in untransfected 1321N1 cells. The pharmacological profile for P2X antagonists to inhibit [3H]A-804598 binding correlated with their ability to block functional activation of P2X7 receptors (r=0.95, PP2X7 receptors described to date and [3H]A-804598 is a high affinity antagonist radioligand that specifically labels rat P2X7 receptors.

  20. Antagonist profile of ibodutant at the tachykinin NK2 receptor in guinea pig isolated bronchi.

    Science.gov (United States)

    Santicioli, Paolo; Meini, Stefania; Giuliani, Sandro; Lecci, Alessandro; Maggi, Carlo Alberto

    2013-10-24

    In this study we have characterized the pharmacological profile of the non-peptide tachykinin NK2 receptor antagonist ibodutant (MEN15596) in guinea pig isolated main bronchi contractility. The antagonist potency of ibodutant was evaluated using the selective NK2 receptor agonist [βAla(8)]NKA(4-10)-mediated contractions of guinea pig isolated main bronchi. In this assay ibodutant (30, 100 and 300nM) induced a concentration-dependent rightward shift of the [βAla(8)]NKA(4-10) concentration-response curves without affecting the maximal contractile effect. The analysis of the results yielded a Schild-plot linear regression with a slope not different from unity (0.95, 95% c.l. 0.65-1.25), thus indicating a surmountable behaviour. The calculated apparent antagonist potency as pKB value was 8.31±0.05. Ibodutant (0.3-100nM), produced a concentration-dependent inhibition of the nonadrenergic-noncholinergic (NANC) contractile response induced by electrical field stimulation (EFS) of intrinsic airway nerves in guinea pig isolated main bronchi. At the highest concentration tested (100nM) ibodutant almost abolished the EFS-induced bronchoconstriction (95±4% inhibition), the calculated IC50 value was 2.98nM (95% c.l. 1.73-5.16nM). In bronchi from ovalbumin (OVA) sensitized guinea pigs ibodutant (100nM) did not affect the maximal contractile response to OVA, but completely prevented the slowing in the fading of the motor response induced by phosphoramidon pretreatment linked to the endogenous neurokinin A release. Altogether, the present study demonstrate that ibodutant is a potent NK2 receptor antagonist in guinea pig airways.

  1. DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles.

    Science.gov (United States)

    Tam, S W; Steinfels, G F; Gilligan, P J; Schmidt, W K; Cook, L

    1992-12-01

    It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP.

    Science.gov (United States)

    Silverman, Jill L; Tolu, Seda S; Barkan, Charlotte L; Crawley, Jacqueline N

    2010-03-01

    Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. BTBR T+tf/J (BTBR) is an inbred mouse strain that shows robust behavioral phenotypes with analogies to all three of the diagnostic symptoms of autism, including well-replicated deficits in reciprocal social interactions and social approach, unusual patterns of ultrasonic vocalization, and high levels of repetitive self-grooming. These phenotypes offer straightforward behavioral assays for translational investigations of pharmacological compounds. Two suggested treatments for autism were evaluated in the BTBR mouse model. Methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor, blocks aberrant phenotypes in the Fmr1 mouse model of Fragile X, a comorbid neurodevelopmental disorder with autistic features. Risperidone has been approved by the United States Food and Drug Administration for the treatment of irritability, tantrums, and self-injurious behavior in autistic individuals. We evaluated the actions of MPEP and risperidone on two BTBR phenotypes, low sociability and high repetitive self-grooming. Open field activity served as an independent control for non-social exploratory activity and motor functions. C57BL/6J (B6), an inbred strain with high sociability and low self-grooming, served as the strain control. MPEP significantly reduced repetitive self-grooming in BTBR, at doses that had no sedating effects on open field activity. Risperidone reduced repetitive self-grooming in BTBR, but only at doses that induced sedation in both strains. No overall improvements in sociability were detected in BTBR after treatment with either MPEP or risperidone. Our findings suggest that antagonists of mGluR5 receptors may have selective therapeutic efficacy in treating repetitive behaviors in autism.

  3. Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs.

    Science.gov (United States)

    Bao, Xiaolu; Zhu, Weibo; Zhang, Ruijing; Wen, Caihong; Wang, Li; Yan, Yijia; Tang, Hesheng; Chen, Zhilong

    2016-05-01

    Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.

  4. Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth.

    Science.gov (United States)

    Chin, Peck Yin; Dorian, Camilla L; Hutchinson, Mark R; Olson, David M; Rice, Kenner C; Moldenhauer, Lachlan M; Robertson, Sarah A

    2016-11-07

    Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (-)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.

  5. Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth

    Science.gov (United States)

    Chin, Peck Yin; Dorian, Camilla L.; Hutchinson, Mark R.; Olson, David M.; Rice, Kenner C.; Moldenhauer, Lachlan M.; Robertson, Sarah A.

    2016-01-01

    Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting. PMID:27819333

  6. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

    Science.gov (United States)

    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  7. Potential benefit from an H1-receptor antagonist on postexercise syncope in the heat.

    Science.gov (United States)

    McCord, Jennifer L; Pellinger, Thomas K; Lynn, Brenna M; Halliwill, John R

    2008-11-01

    H1-receptors mediate the early portion (i.e., first 30 min after exercise) of postexercise hypotension. Immediately after exercise, syncope can occur due to an exaggerated form of postexercise hypotension. Therefore, we hypothesized that orthostatic hypotension occurring immediately after exercise would be attenuated with an H1-receptor antagonist. We studied 15 endurance exercise-trained men and women in an environmental chamber set at 35 degrees C and 30.0% humidity. Subjects were studied in the supine position before a 45-min bout of treadmill running at 50% of VO2max. Immediately after exercise, measurements were taken in the supine position before the subjects were moved from a supine to a 60 degrees head-up tilt. Measurements included arterial pressure, heart rate, and brachial and cutaneous blood flow on a control and an H1-receptor antagonist (blockade) day. Mean arterial pressure was reduced 1 min into the tilt compared with preexercise values on the control day (76.2 +/- 0.5 vs 74.2 +/- 0.5 mm Hg; P 0.41). There were no differences in brachial vascular conductance (calculated as flow/pressure) in response to the head-up tilt between the study days (P > 0.23). The length of the head-up tilt was compared between study days for each subject. When contrasting this difference, the blockade lengthened the mean tilt time by 94 s (P = 0.098). These data suggest that an H1-receptor antagonist could potentially benefit postexercise syncope in a hot environment.

  8. Kinetic modeling of 11C-LY2795050, a novel antagonist radiotracer for PET imaging of the kappa opioid receptor in humans

    OpenAIRE

    Naganawa, Mika; Zheng, Ming-Qiang; Nabulsi, Nabeel; Tomasi, Giampaolo; Henry, Shannan; Lin, Shu-Fei; Ropchan, Jim; Labaree, David; Tauscher, Johannes; Neumeister, Alexander; Carson, Richard E.; Huang, Yiyun

    2014-01-01

    11C-LY2795050 is a novel kappa opioid receptor (KOR) antagonist tracer for positron emission tomography (PET) imaging. The purpose of this first-in-human study was to determine the optimal kinetic model for analysis of 11C-LY2795050 imaging data. Sixteen subjects underwent baseline scans and blocking scans after oral naltrexone. Compartmental modeling and multilinear analysis-1 (MA1) were applied using the arterial input functions. Two-tissue compartment model and MA1 were found to be the bes...

  9. Modification of Anxious Behavior after Psychogenic Trauma and Treatment with Galanin Receptor Antagonist.

    Science.gov (United States)

    Lyudyno, V I; Tsikunov, S G; Abdurasulova, I N; Kusov, A G; Klimenko, V M

    2015-07-01

    Effects of blockage of central galanin receptors on anxiety manifestations were studied in rats with psychogenic trauma. Psychogenic trauma was modeled by exposure of a group of rats to the situation when the partner was killed by a predator. Antagonist of galanin receptors was intranasally administered before stress exposure. Animal behavior was evaluated using the elevated-plus maze test, free exploratory paradigm, and open-field test. Psychogenic trauma was followed by an increase in anxiety level and appearance of agitated behavior. Blockage of galanin receptors aggravated behavioral impairment, which manifested in the pathological anxious reactions - manifestations of hypervigilance and hyperawareness. The results suggest that endogenous pool of galanin is involved into prevention of excessive CNS response to stressful stimuli typical of posttraumatic stress disorder.

  10. New trisubstituted 1,2,4-triazoles as ghrelin receptor antagonists.

    Science.gov (United States)

    Blayo, Anne-Laure; Maingot, Mathieu; Aicher, Babette; M'Kadmi, Céline; Schmidt, Peter; Müller, Gilbert; Teifel, Michael; Günther, Eckhard; Gagne, Didier; Denoyelle, Séverine; Martinez, Jean; Fehrentz, Jean-Alain

    2015-01-01

    Ghrelin receptor ligands based on a trisubstituted 1,2,4-triazole scaffold were recently synthesized and evaluated for their in vitro affinity for the GHS-R1a receptor and their biological activity. In this study, replacement of the α-aminoisobutyryl (Aib) moiety (a common feature present in numerous growth hormone secretagogues described in the literature) by aromatic and heteroaromatic groups was explored. We found potent antagonists incorporating the picolinic moiety in place of the Aib moiety. In an attempt to increase affinity and activity of our lead compound 2, we explored the modulation of the pyridine ring. Herein we report the design and the structure-activity relationships study of these new ghrelin receptor ligands.

  11. Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Prenant, C., E-mail: cprenant@cyclopharma.f [Wolfson Molecular Imaging Centre, University of Manchester, Manchester (United Kingdom); Cawthorne, C. [Academic Department of Radiation Oncology, Christie NHS Foundation Trust, Manchester (United Kingdom); Fairclough, M. [Wolfson Molecular Imaging Centre, University of Manchester, Manchester (United Kingdom); Rothwell, N.; Boutin, H. [Faculty of Life Sciences, University of Manchester, Manchester (United Kingdom)

    2010-09-15

    IL-1RA is a naturally occurring antagonist of the pro-inflammatory cytokine interleukin-1 (IL-1) with high therapeutic promise, but its pharmacokinetic remains poorly documented. In this report, we describe the radiolabeling of recombinant human interleukin-1 receptor antagonist (rhIL-1RA) with fluorine-18 to allow pharmacokinetic studies by positron emission tomography (PET). rhIL-1RA was labeled randomly by reductive alkylation of free amino groups (the {epsilon}-amino group of lysine residues or amino-terminal residues) using [{sup 18}F]fluoroacetaldehyde under mild reaction conditions. Radiosyntheses used a remotely controlled experimental rig within 100 min and the radiochemical yield was in the range 7.1-24.2% (decay corrected, based on seventeen syntheses). We showed that the produced [{sup 18}F]fluoroethyl-rhIL-1ra retained binding specificity by conducting an assay on rat brain sections, allowing its pharmakokinetic study using PET.

  12. [Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS].

    Science.gov (United States)

    Komoto, Shunsuke; Miura, Soichiro

    2006-08-01

    Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.

  13. Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods

    Science.gov (United States)

    Roos, Katarina; Hogner, Anders; Ogg, Derek; Packer, Martin J.; Hansson, Eva; Granberg, Kenneth L.; Evertsson, Emma; Nordqvist, Anneli

    2015-12-01

    In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures.

  14. NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

    Science.gov (United States)

    Dammermann, Werner; Zhang, Bo; Nebel, Merle; Cordiglieri, Chiara; Odoardi, Francesca; Kirchberger, Tanja; Kawakami, Naoto; Dowden, James; Schmid, Frederike; Dornmair, Klaus; Hohenegger, Martin; Flügel, Alexander; Guse, Andreas H.; Potter, Barry V. L.

    2009-01-01

    The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca2+ signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca2+ mobilization by d-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca2+ entry. BZ194 specifically and effectively blocked NAADP-stimulated [3H]ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca2+ mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca2+ mobilization, such as nuclear translocation of “nuclear factor of activated T cells” (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4+ effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases. PMID:19541638

  15. Identification of functional bitter taste receptors and their antagonist in chickens.

    Science.gov (United States)

    Dey, Bapon; Kawabata, Fuminori; Kawabata, Yuko; Yoshida, Yuta; Nishimura, Shotaro; Tabata, Shoji

    2017-01-22

    Elucidation of the taste sense of chickens is important not only for the development of chicken feedstuffs for the chicken industry but also to help clarify the evolution of the taste sense among animals. There are three putative chicken bitter taste receptors, chicken T2R1 (cT2R1), cT2R2 and cT2R7, which were identified using genome information and cell-based assays. Previously, we have shown that cT2R1 is a functional bitter taste receptor through both cell-based assays and behavioral tests. In this study, therefore, we focused on the sensitivities of the other two bitter receptors, cT2R2 and cT2R7, by using their agonists in behavioral tests. We tested three agonists of cT2R2 and three agonists of cT2R7. In a 10-min drinking study, the intakes of cT2R2 agonist solutions were not different from that of water. On the other hand, the intakes of cT2R7 agonist solutions were significantly lower compared to water. In addition, we constructed cT2R1-and cT2R7-expressing cells in order to search for an antagonist for these functional bitter taste receptors. By using Ca(2+) imaging methods, we found that 6-methoxyflavanone (6-meth) can inhibit the activities of both cT2R1 and cT2R7. Moreover, 6-meth also inhibited the reduction of the intake of bitter solutions containing cT2R1 or cT2R7 agonists in behavioral tests. Taken together, these results suggested that cT2R7 is a functional bitter taste receptor like cT2R1, but that cT2R2 is not, and that 6-meth is an antagonist for these two functional chicken bitter taste receptors. This is the first identification of an antagonist of chicken bitter receptors. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. The blockade of GABAA receptors attenuates the inhibitory effect of orexin type 1 receptors antagonist on morphine withdrawal syndrome in rats.

    Science.gov (United States)

    Davoudi, Mahnaz; Azizi, Hossein; Mirnajafi-Zadeh, Javad; Semnanian, Saeed

    2016-03-23

    The aim of present study was to investigate the involvement of orexin-A neuropeptide in naloxone-induced morphine withdrawal syndrome via modulating neurons bearing GABAA receptors. The locus coeruleus (LC) is a sensitive site for expression of the somatic aspects of morphine withdrawal. Intra-LC microinjection of GABAA receptor agonist attenuates morphine withdrawal signs in rats. Here we studied the influence of LC orexin type 1 receptors blockade by SB-334867 in presence of bicuculline, a GABAA receptor antagonist, on naloxone-induced morphine withdrawal syndrome. Adult male Wistar rats, weighing 250-300 g, were rendered dependent on morphine by subcutaneous (s.c.) injection of increasing morphine doses (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at set intervals of 24 h for 7 days. On 8th day, naloxone (3 mg/kg, s.c.) was injected and the somatic signs of morphine withdrawal were evaluated. Intra-LC microinjections (0.2 μl) of either bicuculline (15 μM) or SB-334867 (3 mM) or a combination of both chemicals were done immediately before naloxone injection. Intra-LC microinjection of bicuculline (15 μM) had no significant effect on morphine withdrawal signs, whereas intra-LC microinjection of SB-334867 considerably attenuated morphine withdrawal signs. However, the effect of SB-334867 in attenuating naloxone-induced morphine withdrawal signs was blocked in presence of bicuculline. This finding, for the first time, indicated that orexin-A may participate in expression of naloxone-induced morphine withdrawal syndrome partly through decreasing the activity of neurons bearing GABAA receptors.

  17. Structural model for gamma-aminobutyric acid receptor noncompetitive antagonist binding: widely diverse structures fit the same site.

    Science.gov (United States)

    Chen, Ligong; Durkin, Kathleen A; Casida, John E

    2006-03-28

    Several major insecticides, including alpha-endosulfan, lindane, and fipronil, and the botanical picrotoxinin are noncompetitive antagonists (NCAs) for the GABA receptor. We showed earlier that human beta(3) homopentameric GABA(A) receptor recognizes all of the important GABAergic insecticides and reproduces the high insecticide sensitivity and structure-activity relationships of the native insect receptor. Despite large structural diversity, the NCAs are proposed to fit a single binding site in the chloride channel lumen lined by five transmembrane 2 segments. This hypothesis is examined with the beta(3) homopentamer by mutagenesis, pore structure studies, NCA binding, and molecular modeling. The 15 amino acids in the cytoplasmic half of the pore were mutated to cysteine, serine, or other residue for 22 mutants overall. Localization of A-1'C, A2'C, T6'C, and L9'C (index numbers for the transmembrane 2 region) in the channel lumen was established by disulfide cross-linking. Binding of two NCA radioligands [(3)H]1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane and [(3)H] 3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile was dramatically reduced with 8 of the 15 mutated positions, focusing attention on A2', T6', and L9' as proposed binding sites, consistent with earlier mutagenesis studies. The cytoplasmic half of the beta3 homopentamer pore was modeled as an alpha-helix. The six NCAs listed above plus t-butylbicyclophosphorothionate fit the 2' to 9' pore region forming hydrogen bonds with the T6' hydroxyl and hydrophobic interactions with A2', T6', and L9' alkyl substituents, thereby blocking the channel. Thus, widely diverse NCA structures fit the same GABA receptor beta subunit site with important implications for insecticide cross-resistance and selective toxicity between insects and mammals.

  18. Lack of Association Between IL-1 Receptor Antagonist Gene 86bp VNTR Polymorphism and Leiomyoma

    Directory of Open Access Journals (Sweden)

    Mohammadoo Khorasani

    2014-04-01

    Full Text Available Background Uterine leiomyoma (ULs is the most common gynecological tumor and a significant health concern for many women .The interleukin-1 receptor antagonist (IL-1Ra is a naturally occurring cytokine inhibiting interleukin- 1 (IL-1 activity by binding to the IL-1 receptors without signal transduction. Objectives The aim of this study was to investigate the association between interleukin-1 receptor antagonist gene variable number of tandem repeat (VNTR polymorphism and ULs in women of the South- East of Iran. Patients and Methods A total number of 99 patients with leiomyoma and 102 controls were studied. Genotyping of IL-1Ra (VNTR polymorphism was determined by gel electrophoresis after PCR amplification. Frequency of alleles and genotypes in patients and control group was statistically analyzed using χ2 test or fisher exact test. Results The frequency of alleles 1, 2 and 3 of IL-1Ra VNTR polymorphism were %71, %27 and %22 in control group and %74, %20 and %6 in the ULs patients, respectively and there were no significant differences between these two groups. No statistically significant differences were observed between the frequency of IL-1Ra genotypes in the study and control groups. Conclusions This study showed that 86bp VNTR polymorphism of IL-1Ra gene is not associated with leiomyoma in the studied population.

  19. Triazoloquinazolines as Human A3 Adenosine Receptor Antagonists: A QSAR Study

    Directory of Open Access Journals (Sweden)

    Dae-Sil Lee

    2006-11-01

    Full Text Available Multiple linear regression analysis was performed on the quantitative structure-activity relationships (QSAR of the triazoloquinazoline adenosine antagonists for human A3receptors. The data set used for the QSAR analysis encompassed the activities of 33triazoloquinazoline derivatives and 72 physicochemical descriptors. A template moleculewas derived using the known molecular structure for one of the compounds when bound tothe human A2B receptor, in which the amide bond was in a cis-conformation. All the testcompounds were aligned to the template molecule. In order to identify a reasonable QSARequation to describe the data set, we developed a multiple linear regression program thatexamined every possible combination of descriptors. The QSAR equation derived from thisanalysis indicates that the spatial and electronic effects is greater than that of hydrophobiceffects in binding of the antagonists to the human A3 receptor. It also predicts that a largesterimol length parameter is advantageous to activity, whereas large sterimol widthparameters and fractional positive partial surface areas are nonadvatageous.

  20. Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro.

    Science.gov (United States)

    Zhang, Qiao; Wang, Shifeng; Yu, Yangyang; Sun, Shengnan; Zhang, Yuxin; Zhang, Yanling; Yang, Wei; Li, Shiyou; Qiao, Yanjiang

    2016-08-02

    Endothelin-1 (ET-1) autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR) and endothelin B receptor (ETBR). Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A) is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen), which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC) and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR.

  1. Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.

    Directory of Open Access Journals (Sweden)

    Henrik Keränen

    Full Text Available To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses to drug treatment. For G-protein coupled receptors systematic mutagenesis has provided the major part of functional data as structural information until recently has been very limited. For the pharmacologically important A(2A adenosine receptor, extensive site-directed mutagenesis data on agonist and antagonist binding is available and crystal structures of both types of complexes have been determined. Here, we employ a computational strategy, based on molecular dynamics free energy simulations, to rationalize and interpret available alanine-scanning experiments for both agonist and antagonist binding to this receptor. These computer simulations show excellent agreement with the experimental data and, most importantly, reveal the molecular details behind the observed effects which are often not immediately evident from the crystal structures. The work further provides a distinct validation of the computational strategy used to assess effects of point-mutations on ligand binding. It also highlights the importance of considering not only protein-ligand interactions but also those mediated by solvent water molecules, in ligand design projects.

  2. Lower lid entropion secondary to treatment with alpha-1a receptor antagonist: a case report

    Directory of Open Access Journals (Sweden)

    Simcock Peter

    2010-03-01

    Full Text Available Abstract Introduction The use of alpha-1a receptor antagonists (tamsulosin is widely accepted in the treatment of benign prostatic hypertrophy (BPH. It has previously been implicated as a causative agent in intra-operative floppy iris syndrome due to its effects on the smooth muscle. We report a case of lower lid entropion that may be related to a patient commencing treatment of tamsulosin. Case presentation A 74-year-old Caucasian man was started on alpha 1-a receptor antagonist (Tamsulosin treatment for benign prostatic hypertrophy. Eight days later, he presented to the ophthalmology unit with a right lower lid entropion which was successfully treated surgically with a Weiss procedure. Conclusion We report a case of lower lid entropion that may be secondary to the recent use of an alpha-1a blocker (tamsulosin. This can be explained by considering the effect of autonomic blockade on alpha-1 receptors in the Muller's muscle on a patient that may already have an anatomical predisposition to entropion formation due to a further reduction in muscle tone.

  3. Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo.

    Science.gov (United States)

    Perez, Michel; Lamothe, Marie; Maraval, Catherine; Mirabel, Etienne; Loubat, Chantal; Planty, Bruno; Horn, Clemens; Michaux, Julien; Marrot, Sebastien; Letienne, Robert; Pignier, Christophe; Bocquet, Arnaud; Nadal-Wollbold, Florence; Cussac, Didier; de Vries, Luc; Le Grand, Bruno

    2009-10-08

    Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1. This article describes the discovery of new antagonists of these receptors and more specifically two compounds: 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl]benzonitrile 36 (F 16618) and 3-(2-chlorophenyl)-1-[4-(4-fluorobenzyl)piperazin-1-yl]propenone 39 (F 16357), obtained after optimization. Both compounds are able to inhibit SFLLR-induced human platelet aggregation and display antithrombotic activity in an arteriovenous shunt model in the rat after iv or oral administration. Furthermore, these compounds are devoid of bleeding side effects often observed with other types of antiplatelet drugs, which constitutes a promising advantage for this new class of antithrombotic agents.

  4. Molecular Probes for Muscarinic Receptors: Derivatives of the M1-Antagonist Telenzepine

    Science.gov (United States)

    Karton, Yishai; Baumgold, Jesse; Handen, Jeffrey S.; Jacobson, Kenneth A.

    2012-01-01

    Functionalized congeners of the M1-selective muscarinic antagonist telenzepine (4,9-dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl]-10H-thieno[3,4–b][1,5]benzodiazepin-10-one) were developed and found to bind to the receptor with affinities (Ki values) in approximately the nanomolar range. The derivatives contain a 10-aminodecyl group, which provides a nucleophilic functionality for further derivatization. The attachment of a spacer chain to the distal piperazinyl nitrogen was based on previous findings of enhanced affinity at muscarinic receptors in an analogous series of alkylamino derivatives of pirenzepine [J. Med. Chem. (1991) 34, 2133–2145]. The telenzepine derivatives contain prosthetic groups for radioiodination, protein cross-linking, photoaffinity labeling, and fluorescent labeling and biotin for avidin complexation. The affinity for muscarinic receptors in rat forebrain (mainly m1 subtype) was determined in competitive binding assays vs [3H]-N-methylscopolamine. A (p-aminophenyl)-acetyl derivative for photoaffinity labeling had a Ki value of 0.29 nM at forebrain muscarinic receptors (16-fold higher affinity than telenzepine). A biotin conjugate displayed a Ki value of 0.60 nM at m2-receptors and a 5-fold selectivity versus forebrain. The high affinity of these derivatives makes them suitable for the characterization of muscarinic receptors in pharmacological and spectroscopic studies, for peptide mapping, and for histochemical studies. PMID:1520727

  5. Effects of the neuropeptide S receptor antagonist RTI-118 on abuse-related facilitation of intracranial self-stimulation produced by cocaine and methylenedioxypyrovalerone (MDPV) in rats.

    Science.gov (United States)

    Bonano, Julie S; Runyon, Scott P; Hassler, Carla; Glennon, Richard A; Stevens Negus, S

    2014-11-15

    Neuropeptide S (NPS) is a neurotransmitter that activates the NPS receptor to modulate biological functions including anxiety-like behaviors, feeding, and drug reinforcement. RTI-118 is a novel NPS receptor antagonist that decreased cocaine self-administration in rats at doses that had little or no effect on food-maintained responding. To build on these previous findings, this study examined effects of RTI-118 on cocaine-induced facilitation of intracranial self-stimulation (ICSS) in rats. To provide a context for data interpretation, effects of RTI-118 were compared to effects of the kappa opioid receptor agonist U69,593, because the kappa opioid receptor is another peptide neurotransmitter receptor reported to modulate abuse-related cocaine effects. RTI-118 effects were also examined on ICSS facilitation produced by methylenedioxypyrovalerone (MDPV), a novel designer drug of abuse with some cocaine-like effects. Male Sprague-Dawley rats (n=12) with electrodes targeting the medial forebrain bundle responded under a fixed-ratio 1 schedule for range of brain stimulation frequencies. Under control conditions, brain stimulation maintained a frequency-dependent increase in ICSS rates. Cocaine (1.0-10mg/kg) and MDPV (3.2mg/kg) facilitated ICSS. RTI-118 (3.2-32mg/kg) alone produced little effect on ICSS but dose dependently blocked cocaine-induced ICSS facilitation. U69,593 (0.25-0.5mg/kg) also attenuated cocaine effects, but blockade of cocaine effects was incomplete even at a U69,593 dose that alone depressed ICSS. RTI-118 (32mg/kg) failed to block MDPV-induced ICSS facilitation. These results support further consideration of NPS receptor antagonists as candidate treatments for cocaine abuse and provide evidence for differential effects of a candidate treatment on abuse-related effects of cocaine and MDPV. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. Novel histamine H3 receptor antagonists: affinities in an H3 receptor binding assay and potencies in two functional H3 receptor models.

    OpenAIRE

    Schlicker, E.; Kathmann, M; Reidemeister, S.; Stark, H.; Schunack, W

    1994-01-01

    1. We determined the affinities of ten novel H3 receptor antagonists in an H3 receptor binding assay and their potencies in two functional H3 receptor models. The novel compounds differ from histamine in that the aminoethyl side chain is replaced by a propyl or butyl chain linked to a polar group (amide, thioamide, ester, guanidine, guanidine ester or urea) which, in turn, is connected to a hexocyclic ring or to an alicyclic ring-containing alkyl residue [corrected]. 2. The specific binding o...

  7. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    Science.gov (United States)

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-04-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1-3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

  8. Novel Method for Synthesis of Diarylpyrazole Derivatives as Cannabinoid CB1 Receptor Antagonists

    Institute of Scientific and Technical Information of China (English)

    WU Ying-qiu; ZHENG Guo-jun; WANG Ya-ping; WANG Xiang-jing; XIANG Wen-sheng

    2011-01-01

    A novel and efficient method was developed for the synthesis of diarylpyrazole derivatives as cannabinoid CB1 receptor antagonist via four step reactions. The key step was the synthesis of a diarylpyrazole skeleton, which involved initial condensation of the sodium salt of compound 12 with diazonium compounds, and further cyclization by heating at reflux in acetic acid. Eight diarylpyrazole derivatives and nine new synthesized compounds were cha racterized by 1H NMRy IR, MS, and elemental analysis. The reaction conditions were mild and the overall yields of the target compounds ranged from 26% to 44%.

  9. Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats.

    OpenAIRE

    Kimble, R B; Vannice, J L; Bloedow, D C; Thompson, R.C.; Hopfer, W; Kung, V T; Brownfield, C; Pacifici, R

    1994-01-01

    Interleukin-1 (IL-1), a cytokine produced by bone marrow cells and bone cells, has been implicated in the pathogenesis of postmenopausal osteoporosis because of its potent stimulatory effects on bone resorption in vitro and in vivo. To investigate whether IL-1 plays a direct causal role in post ovariectomy bone loss, 6-mo-old ovariectomized rats were treated with subcutaneous infusions of IL-1 receptor antagonist (IL-1ra), a specific competitor of IL-1, for 4 wk, beginning either at the time ...

  10. NO in exhaled air of asthmatic children is reduced by the leukotriene receptor antagonist montelukast

    DEFF Research Database (Denmark)

    Bisgaard, H; Loland, L; Oj, J A

    1999-01-01

    Nitric oxide in exhaled air (FENO) is increased in asthmatic children, probably reflecting aspects of airway inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) montelukast on FENO with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty......-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial of 2 wk of treatment with 5 mg montelukast once daily versus placebo. FENO was measured during single-breath exhalation at a constant flow rate of 0.1 to 0.13 L/s against a resistance of 10 kPa/L/s. Eleven children were receiving...

  11. The discovery of quinoline based single-ligand human H1 and H3 receptor antagonists.

    Science.gov (United States)

    Procopiou, Panayiotis A; Ancliff, Rachael A; Gore, Paul M; Hancock, Ashley P; Hodgson, Simon T; Holmes, Duncan S; Keeling, Steven P; Looker, Brian E; Parr, Nigel A; Rowedder, James E; Slack, Robert J

    2016-12-15

    A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.

  12. Hydroxylated analogues of 5-aminovaleric acid as 4-aminobutyric acidB receptor antagonists

    DEFF Research Database (Denmark)

    Kristiansen, U; Hedegaard, A; Herdeis, C;

    1992-01-01

    The (R) and (S) forms of 5-amino-2-hydroxyvaleric acid (2-OH-DAVA) and 5-amino-4-hydroxyvaleric acid (4-OH-DAVA) were designed as structural hybrids of the 4-aminobutyric acidB (GABAB) agonist (R)-(-)-4-amino-3-hydroxybutyric acid [(R)-(-)-3-OH-GABA] and the GABAB antagonist 5-aminovaleric acid....... All four compounds were weak inhibitors of GABAA receptor binding in rat brain, and none of them significantly affected synaptosomal GABA uptake. Based on molecular modeling studies it has been demonstrated that low-energy conformations of (R)-(-)-3-OH-GABA, (S)-(-)-2-OH-DAVA, and (R)-(-)-4-OH...

  13. Unusual pyrimidine participation: efficient stereoselective synthesis of potent dual orexin receptor antagonist MK-6096.

    Science.gov (United States)

    Chung, John Y L; Zhong, Yong-Li; Maloney, Kevin M; Reamer, Robert A; Moore, Jeffrey C; Strotman, Hallena; Kalinin, Alexei; Feng, Ronnie; Strotman, Neil A; Xiang, Bangping; Yasuda, Nobuyoshi

    2014-11-21

    An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

  14. Synthesis of inositol phosphate-based competitive antagonists of inositol 1,4,5-trisphosphate receptors

    OpenAIRE

    Konieczny, Vera; Stefanakis, John G.; Sitsanidis, Efstratios; Ioannidou, Natalia-Anastasia T.; Papadopoulos, Nikolaos V.; Fylaktakidou, Konstantina C.; Taylor, Colin W.; Koumbis, Alexandros E.

    2016-01-01

    This is the final version of the article. It first appeared from the Royal Chemistry Society via http://dx.doi.org/10.1039/C5OB02623G Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular Ca²⁺ channels that are widely expressed in animal cells, where they mediate the release of Ca²⁺ from intracellular stores evoked by extracellular stimuli. A diverse array of synthetic agonists of IP3Rs has defined structure-activity relationships, but existing antagonists have severe limitations...

  15. Comparison of the effects of the M1-receptor antagonist telenzepine and the CCK-receptor antagonist loxiglumide on the pancreatic secretory response to intraduodenal tryptophan in dogs.

    Science.gov (United States)

    Teyssen, S; Niebergall-Roth, E; Rausch, A; Beglinger, C; Riepl, R L; Chari, S; Singer, M V

    1996-11-01

    In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses (20.25 to 81.0 nmol/kg/h) of the muscarinic M1-receptor antagonist telenzepine, the cholecystokinin (CCK) antagonist loxiglumide (2.5 to 10.0 mg/kg/h) and several combinations of both drugs on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10.0 mmol/h) given against a background of secretin (20.5 pmol/kg/h i.v.). Except for 20.25 nmol/kg/h telenzepine, all tested doses of telenzepine and/or loxiglumide decreased the 180-min integrated bicarbonate response to tryptophan by 55 to 119%. Except of 20.25 nmol/kg/h telenzepine and/or 2.5 mg/kg/h loxiglumide, all tested doses of telezepine and/or loxiglumide inhibited the tryptophan stimulated integrated pancreatic protein responses by 54 to 88%. While telenzepine mainly inhibited the bicarbonate and protein response to the lower loads of tryptophan (0.37-1.1 mmol/h), loxiglumide decreased the response to all loads of tryptophan. The inhibition evoked by the combinations of telenzepine and loxiglumide was not significantly greater than that by single infusion of either drug. The CCK plasma levels basally and in response to tryptophan were not significantly altered by telenzepine and/or loxiglumide. These findings indicate that (1) both enteropancreatic cholinergic reflexes and the hormone CCK are mediators of the protein response to intraduodenal trytophan (2) enteropancreatic cholinergic reflexes are probably the dominant mediators of the response to low amounts of tryptophan, whereas CCK is the major mediator of the response to high loads of tryptophan, (3) the two mediators seem to act independently of each other, and (4) the release of CCK by intestinal trytophan is not influenced by telenzepine or loxiglumide.

  16. Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Ruhlmann, Christina; Herrstedt, Jørn

    2009-01-01

    , whereas the effect on nausea seems to be limited. The first NK(1) receptor antagonist, aprepitant, became clinically available in 2003, and casopitant, the second in this class of antiemetics, has now completed phase III trials. This review delineates the properties and clinical use of casopitant......-hydroxytryptamine (5-HT)(3)- and neurokinin (NK)(1) receptors in the emetic reflex arch. This has led to the development of two new classes of antiemetics acting as highly selective antagonists at one of these receptors. These drugs have had a huge impact in the protection from chemotherapy-induced vomiting...

  17. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: implications for opioid/cannabinoid interaction studies.

    Science.gov (United States)

    Seely, Kathryn A; Brents, Lisa K; Franks, Lirit N; Rajasekaran, Maheswari; Zimmerman, Sarah M; Fantegrossi, William E; Prather, Paul L

    2012-10-01

    Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (K(i)) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (K(b) = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.

  18. Synthesis of a potent and selective (18)F-labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging.

    Science.gov (United States)

    Ryu, Eun Kyoung; Wu, Zhanhong; Chen, Kai; Lazarus, Lawrence H; Marczak, Ewa D; Sasaki, Yusuke; Ambo, Akihiro; Salvadori, Severo; Ren, Chuancheng; Zhao, Heng; Balboni, Gianfranco; Chen, Xiaoyuan

    2008-03-27

    Identification and pharmacological characterization of two new selective delta-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high delta selectivity, H-Dmt-Tic--Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[ (18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic--Lys(Z)-OH under slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [(18)F]- 1 was about 25-30% ( n = 5) starting from [(18)F]SFB ( n = 5) with an effective specific activity about 46 GBq/micromol. In vitro autoradiography studies showed prominent uptake of [ (18)F]- 1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective delta-opioid receptor antagonist), suggesting high specific binding of [(18)F]- 1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [(18)F]- 1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [ (18)F]- 1 for imaging peripheral delta-opioid receptors.

  19. Discovery of CC chemokine receptor-3 (CCR3) antagonists with picomolar potency.

    Science.gov (United States)

    De Lucca, George V; Kim, Ui Tae; Vargo, Brian J; Duncia, John V; Santella, Joseph B; Gardner, Daniel S; Zheng, Changsheng; Liauw, Ann; Wang, Zhang; Emmett, George; Wacker, Dean A; Welch, Patricia K; Covington, Maryanne; Stowell, Nicole C; Wadman, Eric A; Das, Anuk M; Davies, Paul; Yeleswaram, Swamy; Graden, Danielle M; Solomon, Kimberly A; Newton, Robert C; Trainor, George L; Decicco, Carl P; Ko, Soo S

    2005-03-24

    Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.

  20. Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

    Science.gov (United States)

    Nikolic, Katarina; Filipic, Slavica; Agbaba, Danica; Stark, Holger

    2014-07-01

    The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.

  1. The gain of the baroreflex bradycardia is reduced by microinjection of NMDA receptor antagonists into the nucleus tractus solitarii of awake rats.

    Science.gov (United States)

    Frigero, M; Bonagamba, L G; Machado, B H

    2000-02-14

    The baroreflex activation with phenylephrine infusion produces a bradycardic response. In the present study, the role of NMDA receptors in the nucleus tractus solitarii (NTS) in the processing of the parasympathetic component of the baroreflex was evaluated using acid phosphonivaleric (AP-5), a selective NMDA receptor antagonist. Baroreflex activation was performed before and after bilateral microinjection of AP-5 into the intermediate commissural NTS (0.5 mm lateral to the midline). Microinjection of the vehicle (saline, 0.9%) or a dose of 2 nmol/50 nl of AP-5 into the NTS produced no effect on the gain of the baroreflex while a dose of 10 nmol/50 nl of AP-5 produced a significant reduction in the gain of the baroreflex 2 min after microinjection [-1.43+/-0.22 vs. -0. 43+/-0.03 bpm/mmHg, (n=6)], with a return to control levels 10 min after the microinjections. The dose of 10 nmol/50 nl was selective for NMDA receptors considering that the cardiovascular responses to microinjection of AMPA (0.05 pmol/50 nl), a non-NMDA receptor agonist, were not affected by this dose of AP-5 and the responses to microinjection of NMDA (2 nmol/50 nl) were blocked. The data show that the bradycardic response to baroreflex activation was blocked by AP-5 microinjected into the NTS, indicating that the neurotransmission of the parasympathetic component of the baroreflex is mediated by NMDA receptors in the NTS.

  2. Effects of the 5-HT(6) receptor antagonist Ro 04-6790 on learning consolidation.

    Science.gov (United States)

    Meneses, A

    2001-01-08

    The 5-HT(6) receptor antagonist Ro-04-6790 or 8-OH-DPAT injection improved learning consolidation on an autoshaping task, while mCPP, scopolamine and dizocilpine decreased the performance. The effect induced by scopolamine, but not that induced by mCPP, was reversed completely by Ro-04-6790, while dizocilpine effect was antagonized partially. Nevertheless, ritanserin or WAY 100635, but not Ro 04-6790, antagonized the 8-OH-DPAT facilitatory effects on learning consolidation. As WAY 100635 did not modify the Ro 04-6790 facilitatory effect, hence 5-HT(1A), and/or 5-HT(7), but not 5-HT(6), receptors might mediate the 8-OH-DPAT facilitatory effect on learning consolidation. Since, the Ro 04-6790 facilitatory effect was unaffected by 5-HT(1A), 5-HT(2A)/(2B)/(2C), 5-HT(3) or 5-HT(4) receptor blockade, thereby, the facilitatory effect induced by Ro 04-6790 involved specifically 5-HT(6) receptors. Indeed, the present data provide further support to the notion that, 5-HT(6) receptors play a significant part in the learning consolidation under normal and dysfunctional memory conditions.

  3. Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists.

    Science.gov (United States)

    Mohsen, Amal M Y; Mandour, Yasmine M; Sarukhanyan, Edita; Breitinger, Ulrike; Villmann, Carmen; Banoub, Maha M; Breitinger, Hans-Georg; Dandekar, Thomas; Holzgrabe, Ulrike; Sotriffer, Christoph; Jensen, Anders A; Zlotos, Darius P

    2016-12-23

    A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1β glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [(3)H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1β antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.

  4. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    Science.gov (United States)

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.

  5. DIFFERENTIAL BINDING OF HUMAN INTERLEUKIN-1 (IL-1) RECEPTOR ANTAGONIST TO NATURAL AND RECOMBINANT SOLUBLE AND CELLULAR IL-1 TYPE-I RECEPTORS

    DEFF Research Database (Denmark)

    Svenson, Morten; Nedergaard, Susanne; Heegaard, Peter M. H.

    1995-01-01

    antagonist (IL-1ra). Recombinant soluble human IL-1RI expressed in COS cells (sIL-1RI) consists of the extracellular part of the receptor and binds all three known IL-1 species but preferentially to IL-1ra. We further characterized the sizes and binding of IL-1raBF and sIL-1RI to IL-1ra by polyacrylamide gel...... fibroblasts and the interference afforded by the soluble receptors. The results show that the protein backbones of IL-1raBF and sIL-1RI are of similar size (approximate to 35-40 kDa) and that there are differences in the glycosylation of the two molecules. These carbohydrates were necessary for optimal...... binding of both molecules to IL-1ra. Both factors blocked binding of IL-1ra to cellular IL-1RI, as did mAb to IL-1ra, but the sites on IL-1ra which bound to the mAb, and to IL-1raBF and sIL-1RI, differed. We conclude that there are important differences between the natural and recombinant forms of soluble...

  6. Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist

    OpenAIRE

    Hagan, Jim J.; Price, Gary W; Jeffrey, Phillip; Deeks, Nigel J; Stean, Tania; Piper, David; Smith, Martin I; Upton, Neil; Medhurst, Andrew D; Middlemiss, Derek N; Riley, Graham J; Lovell, Peter J; Bromidge, Steven M; Thomas, David R.

    2000-01-01

    The novel 5-HT7 receptor antagonist, SB-269970-A, potently displaced [3H]-5-CT from human 5-HT7(a) (pKi 8.9±0.1) and 5-HT7 receptors in guinea-pig cortex (pKi 8.3±0.2).5-CT stimulated adenylyl cyclase activity in 5-HT7(a)/HEK293 membranes (pEC50 7.5±0.1) and SB-269970-A (0.03–1 μM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA2 (8.5±0.2) for SB-269970-A agreed well with the pKi determined from [3H]-5-CT binding studies.5-CT-stimulated...

  7. Recent advances in the development of dopamine D3 receptor antagonists: a medicinal chemistry perspective.

    Science.gov (United States)

    Micheli, Fabrizio

    2011-07-04

    Dopamine (DA) D(3) receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D(3) receptor antagonists have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemists in this field over the last ten years towards the identification of truly selective compounds. Both primary and patent literature is reviewed here. Since the original discoveries, a clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Examples of advanced leads from academia and industry are described. The latest potential therapeutic applications are reported too.

  8. Estrogen receptor agonists/antagonists in breast cancer therapy: A critical review.

    Science.gov (United States)

    Jameera Begam, A; Jubie, S; Nanjan, M J

    2017-04-01

    Estrogens display intriguing tissue selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer. There are also strong evidences to show that both endogenous and exogenous estrogens are involved in the pathogenesis of breast cancer. Tamoxifen has been the only drug of choice for more than 30years to treat patients with estrogen related (ER) positive breast tumors. There is a need therefore, for identifying newer, potential and novel candidates for breast cancer. Keeping this in view, the present review focuses on selective estrogen receptor modulators and estrogen antagonists such as sulfatase and aromatase inhibitors involved in breast cancer therapy. A succinct and critical overview of the structure of estrogen receptors, their signaling and involvement in breast carcinogenesis are herein described. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Characterization of SB-269970-A, a selective 5-HT7 receptor antagonist

    OpenAIRE

    Hagan, Jim J; Price, Gary W; Jeffrey, Phillip; Deeks, Nigel J; Stean, Tania; Piper, David; Smith, Martin I.; Upton, Neil; Medhurst, Andrew D.; Middlemiss, Derek N; Riley, Graham J; Lovell, Peter J; Bromidge, Steven M; Thomas, David R.

    2000-01-01

    The novel 5-HT7 receptor antagonist, SB-269970-A, potently displaced [3H]-5-CT from human 5-HT7(a) (pKi 8.9±0.1) and 5-HT7 receptors in guinea-pig cortex (pKi 8.3±0.2).5-CT stimulated adenylyl cyclase activity in 5-HT7(a)/HEK293 membranes (pEC50 7.5±0.1) and SB-269970-A (0.03–1 μM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA2 (8.5±0.2) for SB-269970-A agreed well with the pKi determined from [3H]-5-CT binding studies.5-CT-stimulated...

  10. De novo analysis of receptor binding affinity data of xanthine adenosine receptor antagonists.

    Science.gov (United States)

    Dalpiaz, A; Gardenghi, A; Borea, P A

    1995-03-01

    The receptor binding affinity data to adenosine A1 and A2 receptors of a wide series of xanthine derivatives have been analyzed by means of the Free-Wilson model. The analysis of the individual group contribution shows, for both A1 and A2 receptors, the primary importance of the presence of bulky substituents at position 8 for an optimum receptor binding. Moreover, considering the different aij contributions of bulky substituents at position 8 for affinity to A1 with respect to A2 receptors, this position appears to be the most important for the synthesis of highly A1 selective xanthine derivatives. Moreover the analysis of group contributions for other substitution positions of the xanthine moiety allows to state that suitable substitutions at positions 3 and 7 could confer some degree of A2 selectivity.

  11. Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy.

    Science.gov (United States)

    Saito, Shun; Fujimaki, Takahiro; Panbangred, Watanalai; Igarashi, Yasuhiro; Imoto, Masaya

    2016-02-18

    Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.

  12. Receptor-mediated binding and uptake of GnRH agonist and antagonist by pituitary cells

    Energy Technology Data Exchange (ETDEWEB)

    Jennes, L.; Stumpf, W.E.; Conn, P.M.

    1984-01-01

    The intracellular pathway of an enzyme resistant GnRH agonist (D- Lys6 -GnRH) conjugated to ferritin or to colloidal gold was followed in cultured pituitary cells. After an initial uniform distribution over the cell surface of gonadotropes, the electrondense marker was internalized, either individually or in small groups. After longer incubation times, the marker appeared in the lysosomal compartment and the Golgi apparatus, where it could be found in the vesicular as well as cisternal portion. In addition, the receptor-mediated endocytosis of the GnRH antagonist D-p-Glu1-D-Phe2-D-Trp3-D- Lys6 -GnRH was studied by light and electron microscopic autoradiography after 30 and 60 min of incubation to ensure uptake. At both time points, in in vitro as well as in vivo studies, silver grains were localized over cytoplasmic organelles of castration cells, including dilated endoplasmic reticulum, lysosomes, and clear vesicles. No consistent association with cell nuclei, mitochondria, or secretory vesicles could be observed. The results suggest that both agonist and antagonist are binding selectively to the plasma membrane of gonadotropes and subsequently are taken up via receptor-mediated endocytosis for degradation or possible action on synthetic processes.

  13. Cysteinyl Leukotriene Receptor-1 Antagonists as Modulators of Innate Immune Cell Function

    Directory of Open Access Journals (Sweden)

    A. J. Theron

    2014-01-01

    Full Text Available Cysteinyl leukotrienes (cysLTs are produced predominantly by cells of the innate immune system, especially basophils, eosinophils, mast cells, and monocytes/macrophages. Notwithstanding potent bronchoconstrictor activity, cysLTs are also proinflammatory consequent to their autocrine and paracrine interactions with G-protein-coupled receptors expressed not only on the aforementioned cell types, but also on Th2 lymphocytes, as well as structural cells, and to a lesser extent neutrophils and CD8+ cells. Recognition of the involvement of cysLTs in the immunopathogenesis of various types of acute and chronic inflammatory disorders, especially bronchial asthma, prompted the development of selective cysLT receptor-1 (cysLTR1 antagonists, specifically montelukast, pranlukast, and zafirlukast. More recently these agents have also been reported to possess secondary anti-inflammatory activities, distinct from cysLTR1 antagonism, which appear to be particularly effective in targeting neutrophils and monocytes/macrophages. Underlying mechanisms include interference with cyclic nucleotide phosphodiesterases, 5′-lipoxygenase, and the proinflammatory transcription factor, nuclear factor kappa B. These and other secondary anti-inflammatory mechanisms of the commonly used cysLTR1 antagonists are the major focus of the current review, which also includes a comparison of the anti-inflammatory effects of montelukast, pranlukast, and zafirlukast on human neutrophils in vitro, as well as an overview of both the current clinical applications of these agents and potential future applications based on preclinical and early clinical studies.

  14. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention

    DEFF Research Database (Denmark)

    Ho, Tony W; Connor, Kathryn M; Zhang, Ying

    2014-01-01

    OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migra......OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3......-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following...... a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all...

  15. Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas.

    Science.gov (United States)

    Carriero, Maria Vincenza; Bifulco, Katia; Ingangi, Vincenzo; Costantini, Susan; Botti, Giovanni; Ragone, Concetta; Minopoli, Michele; Motti, Maria Letizia; Rea, Domenica; Scognamiglio, Giosuè; Botti, Gerardo; Arra, Claudio; Ciliberto, Gennaro; Pessi, Antonello

    2017-05-02

    The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target. We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis. To develop enzyme-resistant analogues, we applied here the Retro-Inverso (RI) approach, whereby the topology of the side chains is maintained by inverting the sequence of the peptide and the chirality of all residues. Molecular dynamics suggests that peptide RI-3 adopts the turn structure typical of uPAR-FPR1 antagonists. Accordingly, RI-3 is a nanomolar competitor of N-formyl-Met-Leu-Phe for binding to FPR1 and inhibits migration, invasion, trans-endothelial migration of sarcoma cells and VEGF-triggered endothelial tube formation. When sarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density, circulating tumor cells and pulmonary metastases were significantly reduced in animals treated daily with 6 mg/Kg RI-3 as compared to animals treated with vehicle only. Thus, RI-3 represents a promising lead for anti-metastatic drugs.

  16. A new sensitive flow-injection chemiluminescence method for the determination of H(2)-receptor antagonists.

    Science.gov (United States)

    Tang, Yu-Hai; Wang, Nan-Nan; Xiong, Xun-Yu; Xiong, Feng-Mei; Sun, Si-Juan

    2007-01-01

    Based on the chemiluminescence (CL) intensity generated from the potassium ferricyanide [K(3)Fe(CN)(6)]-rhodamine 6G system in sodium hydroxide (NaOH) medium, a new sensitive flow-injection chemiluminescence (FI-CL) method has been developed, validated and applied for the determination of three kinds of H(2)-receptor antagonists: cimetidine (CIMT), ranitidine (RANT) hydrochloride and famotidine (FAMT). Under the optimum conditions, the linear range for the determination was 1.0 x 10(-9)-7.0 x 10(-5) g/ml for CIMT, 1.0 x 10(-9)-5.0 x 10(-5) g/mL for RANT hydrochloride and 5.0 x 10(-9)-7.0 x 10(-5) g/mL for FAMT. During 11 repeated measurements of 1.0 x 10(-6) g/mL sample solutions, the relative standard deviations (RSDs) were all <5%. The detection limit was 8.56 x 10(-10) g/mL for CIMT, 8.69 x 10(-10) g/mL for RANT hydrochloride and 2.35 x 10(-9) g/mL for FAMT (S:N = 3). This method has been successfully implemented for the analysis of H(2)-receptor antagonists in pharmaceuticals.

  17. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

    Science.gov (United States)

    Tritos, Nicholas A; Biller, Beverly M K

    2017-02-01

    To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

  18. Interleukin-1 receptor antagonist gene polymorphism and mortality in patients with severe sepsis

    Science.gov (United States)

    ARNALICH, F; LÓPEZ-MADERUELO, D; CODOCEO, R; LOPEZ, J; SOLIS-GARRIDO, L M; CAPISCOL, C; FERNANDEZ-CAPITÁN, C; MADERO, R; MONTIEL, C

    2002-01-01

    This study aims to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1RN*) on the outcome of severe sepsis, and to assess its functional significance by correlating this polymorphism with the total production of interleukin-1 receptor antagonist (IL-1Ra) protein determined in stimulated peripheral blood mononuclear cells (PBMC). A group of 78 patients with severe sepsis (51 survivors and 27 nonsurvivors) was compared with a healthy control group of 130 blood donors, and 56 patients with uncomplicated pneumonia. We found a significant association between IL-1RN* polymorphism and survival. Thus, after adjusting for age and APACHE II score, multiple logistic regression analysis showed that patients homozygotes for the allele *2 had a 6·47-fold increased risk of death (95% CI 1·01–41·47, P = 0·04). Besides, compared with patients homozygous or heterozygous for the allele *1, IL-1RN*2 homozygotes produced significantly lower levels of IL-1Ra from their PBMC. Our results suggest that insufficient production of this cytokine might contribute, among other factors, to the higher mortality rate found in severe sepsis patients with the IL-1RN*2 homozygous genotype. PMID:11876758

  19. Discriminating agonist and antagonist ligands of the nuclear receptors using 3D-pharmacophores.

    Science.gov (United States)

    Lagarde, Nathalie; Delahaye, Solenne; Zagury, Jean-François; Montes, Matthieu

    2016-01-01

    Nuclear receptors (NRs) constitute an important class of therapeutic targets. We evaluated the performance of 3D structure-based and ligand-based pharmacophore models in predicting the pharmacological profile of NRs ligands using the NRLiSt BDB database. We could generate selective pharmacophores for agonist and antagonist ligands and we found that the best performances were obtained by combining the structure-based and the ligand-based approaches. The combination of pharmacophores that were generated allowed to cover most of the chemical space of the NRLiSt BDB datasets. By screening the whole NRLiSt BDB on our 3D pharmacophores, we demonstrated their selectivity towards their dedicated NRs ligands. The 3D pharmacophores herein presented can thus be used as a predictor of the pharmacological activity of NRs ligands.Graphical AbstractUsing a combination of structure-based and ligand-based pharmacophores, agonist and antagonist ligands of the Nuclear Receptors included in the NRLiSt BDB database could be separated.

  20. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.

    Science.gov (United States)

    Glicklich, Daniel; Frishman, William H

    2015-04-01

    Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

  1. Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB1 receptor antagonist.

    Science.gov (United States)

    Botanas, Chrislean Jun; de la Peña, June Bryan; Dela Pena, Irene Joy; Tampus, Reinholdgher; Kim, Hee Jin; Yoon, Seong Shoon; Seo, Joung-Wook; Jeong, Eun Ju; Cheong, Jae Hoon

    2015-11-01

    AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB1 receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB1 receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague-Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5mg/kg), SA (0.005, 0.025 or 0.1mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naïve rats. Interestingly, significant CPP (0.5mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.

  2. Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents.

    Science.gov (United States)

    Murai, Nobuhito; Hiyama, Hideki; Kiso, Tetsuo; Sekizawa, Toshihiro; Watabiki, Tomonari; Oka, Hiromasa; Aoki, Toshiaki

    2017-08-30

    Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE2-, PGF2α-, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE2-induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Quantitative Electroencephalography Within Sleep/Wake States Differentiates GABAA Modulators Eszopiclone and Zolpidem From Dual Orexin Receptor Antagonists in Rats

    Science.gov (United States)

    Fox, Steven V; Gotter, Anthony L; Tye, Spencer J; Garson, Susan L; Savitz, Alan T; Uslaner, Jason M; Brunner, Joseph I; Tannenbaum, Pamela L; McDonald, Terrence P; Hodgson, Robert; Yao, Lihang; Bowlby, Mark R; Kuduk, Scott D; Coleman, Paul J; Hargreaves, Richard; Winrow, Christopher J; Renger, John J

    2013-01-01

    Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague–Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep. PMID:23722242

  4. Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats.

    Science.gov (United States)

    Fox, Steven V; Gotter, Anthony L; Tye, Spencer J; Garson, Susan L; Savitz, Alan T; Uslaner, Jason M; Brunner, Joseph I; Tannenbaum, Pamela L; McDonald, Terrence P; Hodgson, Robert; Yao, Lihang; Bowlby, Mark R; Kuduk, Scott D; Coleman, Paul J; Hargreaves, Richard; Winrow, Christopher J; Renger, John J

    2013-11-01

    Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.

  5. Effects of estrogen receptor antagonist on biological behavior and expression of growth factors in the prolactinoma MMQ cell line.

    Science.gov (United States)

    Lv, Hongtao; Li, Chuzhong; Gui, Songbai; Sun, Meizhen; Li, Dan; Zhang, Yazhuo

    2011-04-01

    The relationship between estrogen and pituitary prolactinoma is well documented. The biological effects of estrogen are mainly mediated by estrogen receptor α (ERα). Several lines of evidence demonstrate that growth factors such as pituitary tumor transforming gene (PTTG), basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGFβ1), transforming growth factor β3 (TGFβ3), and transforming growth factor β receptor type II (TGFβRII) play an important role in prolactinoma pathogenesis induced by estrogen, but the relationship between ERα and such growth factors is still unclear. The aims of this study are to investigate the functional role of ERα in proliferation, prolactin (PRL) secretion, and expression of the above-mentioned growth factors in MMQ cells in the absence of estrogen and to discuss the feasibility of using an estrogen receptor antagonist to treat prolactinoma. Fulvestrant, a "pure" antiestrogen without any estrogen-like activity, was used to block expression of ERα in the MMQ cell line. Proliferation and PRL secretion of MMQ cells were measured using CellTiter 96(®) AQueous One Solution Cell Proliferation Assay (MTS) and the enzyme-linked immunosorbent assay (ELISA) method. Levels of ERα, PTTG, bFGF, TGFβ1, TGFβ3, and TGFβRII were analyzed by real-time polymerase chain reaction (PCR) and Western blot. Fulvestrant significantly inhibited cell proliferation (up to 60.80%) and PRL secretion (up to 77.95%), and changed expression of TGFβ3 and TGFβRII in the absence of estrogen. In conclusion, ERα plays an important functional role in proliferation and PRL secretion of pituitary prolactinomas and also can change expression of some growth factors even under the condition of no estrogen. Fulvestrant could potentially be an effective therapy for treating such tumors.

  6. Renoprotective effects of a combined endothelin type A/type B receptor antagonist in experimental malignant hypertension.

    Science.gov (United States)

    Kohno, M; Yokokawa, K; Yasunari, K; Kano, H; Minami, M; Ueda, M; Tatsumi, Y; Yoshikawa, J

    1997-09-01

    We previously showed that plasma endothelin-1 (ET-1) concentration was increased in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension in spontaneously hypertensive rats (SHR). In contrast, in normal SHR, this value is similar to that seen in Wistar-Kyoto (WKY) rats. The purpose of this study was to examine the effects of the new combined ET type A/type B (ETA/B) receptor antagonist, TAK-044, on the development of hypertension in this model of malignant hypertension. TAK-044 10 mg/kg, which effectively blocks both ETA and ETB receptors, was administered intraperitoneally once per day for 4 weeks in DOCA-salt SHR, and the effects on ET-1 and other parameters were compared with the same values in untreated WKY rats, untreated DOCA-salt SHR, and hydralazine-treated DOCA-salt SHR. DOCA-salt caused marked increases in blood pressure, blood urea nitrogen (BUN), serum creatinine, and plasma ET-1 concentrations in SHR. Both TAK-044 and hydralazine significantly suppressed the increase in blood pressure in DOCA-salt SHR to the same extent. Both treatments also suppressed the increase in BUN and serum creatinine, but this attenuation was less marked with hydralazine than with TAK-044. Neither TAK-044 nor hydralazine affected plasma ET-1 concentration in this model. TAK-044 significantly reduced kidney weight in DOCA-salt SHR, whereas the decrease seen with hydralazine was less marked. Prevention of DOCA-salt-induced renal structural injury (mesangial hypercellularity, glomerular sclerotic changes, and tubulointerstitial damage) in this model was clearly greater with TAK-044 treatment than with hydralazine treatment. These results suggest that endogenous ET-1 may, at least in part, contribute to renal functional and structural damage in malignant DOCA-salt SHR. Our results raise the possibility of renoprotective effects of ETA/B receptor blockers in certain forms of malignant hypertension.

  7. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2014-12-01

    combination of mifepristone and enzalutamide has been well tolerated with no dose limiting toxicities . The current cohort has dose- escalated the...Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer...Antagonist Mifepristone Combined with Enzalutamide in Castrate-Resistant Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0021 5c. PROGRAM ELEMENT

  8. Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule glucagon receptor antagonist.

    Directory of Open Access Journals (Sweden)

    James Mu

    Full Text Available Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.

  9. An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

    Science.gov (United States)

    Holman, M E; Surprenant, A

    1980-01-01

    1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

  10. The Effects of Serotonin Receptor Antagonists on Contraction and Relaxation Responses Induced by Electrical Stimulation in the Rat Small Intestine

    Directory of Open Access Journals (Sweden)

    Farajian Mashhadi

    2014-03-01

    Full Text Available Background The main source of 5-HT in body is in enterchromafin cells of intestine, different studies mentioned different roles for endogenous 5-HT and receptors involved and it is not clearified the mechanism of action of endogenous 5-HT. Objectives To study the role of endogenous 5-HT on modulation of contraction and relaxation responses induced by electrical field stimulation (EFS in different regions of the rat intestine. Materials and Methods Segments taken from the rat duodenum, jejunum, mid and terminal ileum were vertically mounted, connected to a transducer and exposed to EFS with different frequencies in the absence and presence of various inhibitors of enteric mediators i. e. specific 5-HT receptor antagonists. Results EFS-induced responses were sensitive to TTX and partly to atropine, indicating a major neuronal involvement and a cholinergic system. Pre-treatment with WAY100635 (a 5-HT1A receptor antagonist and granisetron up to 10.0 µM, GR113808 (a 5-HT4 receptor antagonist, methysergide and ritanserin up to 1.0 µM, failed to modify responses to EFS inall examined tissues. In the presence of SB258585 1.0 µM (a 5-HT6 receptor antagonist there was a trend to enhance contraction in the proximal part of the intestine and reduce contraction in the distal part. Pre-treatment with SB269970A 1.0 µM (5-HT7 receptor antagonist induced a greater contractile response to EFS at 0.4 Hz only in the duodenum. Conclusions The application of 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT6 and 5-HT7 receptor antagonists, applied at concentrations lower than 1.0 µM did not modify the EFS-induced contraction and relaxation responses, whichsuggests the unlikely involvement of endogenous 5-HT in mediating responses to EFS in the described test conditions.

  11. Receptors and Channels Targeted by Synthetic Cannabinoid Receptor Agonists and Antagonists

    OpenAIRE

    Pertwee, R. G.

    2010-01-01

    It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders. Just a few of these disorders are already treated with Δ9-tetrahydrocannabinol or nabilone, both CB1/CB2 receptor agonists, and there is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor ago...

  12. Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs*

    Science.gov (United States)

    Pediani, John D.; Ward, Richard J.; Godin, Antoine G.; Marsango, Sara

    2016-01-01

    Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands are unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by using spatial intensity distribution analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules·μm−2 human muscarinic M1 receptor identified a ∼75:25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked up-regulation of the receptor, simple mass action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population, but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior. PMID:27080256

  13. Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs.

    Science.gov (United States)

    Pediani, John D; Ward, Richard J; Godin, Antoine G; Marsango, Sara; Milligan, Graeme

    2016-06-17

    Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands are unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by using spatial intensity distribution analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules·μm(-2) human muscarinic M1 receptor identified a ∼75:25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked up-regulation of the receptor, simple mass action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population, but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Novel benzamide-based histamine h3 receptor antagonists: the identification of two candidates for clinical development.

    Science.gov (United States)

    Letavic, Michael A; Aluisio, Leah; Apodaca, Richard; Bajpai, Manoj; Barbier, Ann J; Bonneville, Anne; Bonaventure, Pascal; Carruthers, Nicholas I; Dugovic, Christine; Fraser, Ian C; Kramer, Michelle L; Lord, Brian; Lovenberg, Timothy W; Li, Lilian Y; Ly, Kiev S; Mcallister, Heather; Mani, Neelakandha S; Morton, Kirsten L; Ndifor, Anthony; Nepomuceno, S Diane; Pandit, Chennagiri R; Sands, Steven B; Shah, Chandra R; Shelton, Jonathan E; Snook, Sandra S; Swanson, Devin M; Xiao, Wei

    2015-04-09

    The preclinical characterization of novel phenyl(piperazin-1-yl)methanones that are histamine H3 receptor antagonists is described. The compounds described are high affinity histamine H3 antagonists. Optimization of the physical properties of these histamine H3 antagonists led to the discovery of several promising lead compounds, and extensive preclinical profiling aided in the identification of compounds with optimal duration of action for wake promoting activity. This led to the discovery of two development candidates for Phase I and Phase II clinical trials.

  15. Therapeutic effect of ifenprodil,a NMDA receptor antagonist,on drug dependence

    Institute of Scientific and Technical Information of China (English)

    SuzukT; NaritM

    2002-01-01

    Although drug dependence has been treated by the adonist-therapy,the specific drug therapy for drug dependence has not been established.Ifenprodil is consibdred to specifically block the NMDA receptor consisted of NR1/NR2B subunits without undesirable adverse reactions,such as psychotomimetic action and psychological dependence,while ketamine and MK-801 can block both NMDA receptors consisted of NR1/NR2A and NR1/NR2B subunits with the undesirable adverse reactions.In the present study,we designed to examine the effect of ifenprodil on drug dependence in rodents.Pretreatment with ifenprodil suppressed the expression of withdrawal signs in morphine-, diazepam-and alcohol-dependent rats and mics.Rewarding effects of morphine,methamphetamine and cocaine as well as physical dependence,were suppressed by pretreatment with ifenprodil in rats and mice.These results suggest that ifenprodil be useful in treating drug dependence.

  16. Combined histamine H1/H2 receptor antagonists: part I. Pharmacological hybrids with pheniramine- and roxatidine-like substructures.

    Science.gov (United States)

    Schulze, F R; Buschauer, A; Schunack, W

    1998-07-01

    A series of hybrid compounds combining the pharmacophores of both pheniramine-type histamine H1 receptor antagonists and roxatidine-type H2 receptor antagonists have been synthesized and tested for histamine antagonism at the isolated ileum (H1) and the spontaneously beating right atrium (H2) of the guinea pig. The 'polar group' of the H2 antagonist moiety (cyanoguanidine, nitroethenediamine or urea) and the side chain amino group of the H1 antagonist portion have been linked by a polymethylene spacer or by a piperazine system. The incorporation of a flexible spacer (2-7 methylene groups) resulted in H1 antagonists achieving up to 2.4 times the activity of pheniramine. Depending on the nature of the polar group the highest H2 antagonist potency resides in compounds with spacers ?2 methylene groups. Nitroethenediamine 24c with a seven-membered chain and a chlorpheniramine substructure proved to be approximately equipotent with pheniramine at the H1 and with ranitidine at the H2 receptor (pKB values 7.82 and 7.1, respectively).

  17. Species-specific action of (Pro3)GIP - an efficacious agonist on human GIP receptor, but partial agonist and competitive antagonist on rat and mouse GIP receptors

    DEFF Research Database (Denmark)

    Sparre-Ulrich, A H; Hansen, Lærke Smidt; Svendsen, B

    2016-01-01

    BACKGROUND AND PURPOSE: Specific high potent receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist (Pro3)GIP and its e...... level. Thus, in rodent models human GIP is a comparatively weak partial agonist. Human (Pro3)GIP is not an effective antagonist, so there is still a need for an effective antagonist for the elucidation of GIP's physiology.......BACKGROUND AND PURPOSE: Specific high potent receptor antagonists are valuable tools when evaluating animal and human physiology. Within the glucose-dependent insulinotropic polypeptide (GIP) system, considerable attention has been given to the presumed GIP receptor antagonist (Pro3)GIP and its...... effect in murine studies. We conducted a pharmacological analysis of this ligand including interspecies differences between the rodent and human GIP system. EXPERIMENTAL APPROACH: Transiently transfected COS-7 cells were assessed for cAMP accumulation upon ligand stimulation and assayed in competition...

  18. Structure-Based Understanding of Binding Affinity and Mode of Estrogen Receptor α Agonists and Antagonists

    Science.gov (United States)

    Barron, Mace G.

    2017-01-01

    The flexible hydrophobic ligand binding pocket (LBP) of estrogen receptor α (ERα) allows the binding of a wide variety of endocrine disruptors. Upon ligand binding, the LBP reshapes around the contours of the ligand and stabilizes the complex by complementary hydrophobic interactions and specific hydrogen bonds with the ligand. Here we present a framework for quantitative analysis of the steric and electronic features of the human ERα-ligand complex using three dimensional (3D) protein-ligand interaction description combined with 3D-QSAR approach. An empirical hydrophobicity density field is applied to account for hydrophobic contacts of ligand within the LBP. The obtained 3D-QSAR model revealed that hydrophobic contacts primarily determine binding affinity and govern binding mode with hydrogen bonds. Several residues of the LBP appear to be quite flexible and adopt a spectrum of conformations in various ERα-ligand complexes, in particular His524. The 3D-QSAR was combined with molecular docking based on three receptor conformations to accommodate receptor flexibility. The model indicates that the dynamic character of the LBP allows accommodation and stable binding of structurally diverse ligands, and proper representation of the protein flexibility is critical for reasonable description of binding of the ligands. Our results provide a quantitative and mechanistic understanding of binding affinity and mode of ERα agonists and antagonists that may be applicable to other nuclear receptors. PMID:28061508

  19. Docking-based virtual screening of potential human P2Y12 receptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Hua Chen; Xianchi Dong; Minyun Zhou; Haiming Shi; Xinping Luo

    2011-01-01

    Platelet plays essential roles in hemostasis and its dysregulation can lead to arterial thrombosis. P2Y12 is an important platelet membrane adenosine diphosphate receptor,and its antagonists have been widely developed as anticoagulation agents. The current P2Y12 inhibitors available in clinical practice have not fully achieved saOsfactory antithrombotic effects, leaving room for further improvement To identify new chemical compounds as potential anticoagulation inhibitors, we constructed a three-dimensional structure model of human P2Y12 by homology modeling based on the recently reported G-protein coupled receptor Meleagris gallopavo βl adrenergic receptor. Virtual screening of the modeled P2Y12 against three subsets of small molecules from the ZINC database, namely lead-like, fragment-like, and drug-like, identified a number of compounds tbat might have high binding affinity to P2Y12.Detailed analyses of the top three compounds from each subset with the highest scores indicated that all of these compounds beard a hydrophobic bulk supplemented with a few polar atoms which bound at the ligand binding site via largely hydrophobic interactions with the receptor. This study not only provides a structure model of P2Y12 for rational design of anti-platelet inhibitors, but also identifies some potential chemicals for further development.

  20. Exploration of structure-activity relationships for dual serotonin transporter reuptake inhibitors-histamine H3 receptor antagonists.

    Science.gov (United States)

    Stocking, Emily M; Letavic, Michael A; Bonaventure, Pascal; Carruthers, Nicholas I

    2010-01-01

    Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H(3) receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H(3) receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H(3) receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.

  1. Inhibition of a slow synaptic response by a metabotropic glutamate receptor antagonist in hippocampal CA3 pyramidal cells.

    Science.gov (United States)

    Gerber, U; Lüthi, A; Gähwiler, B H

    1993-11-22

    The effects of a novel antagonist of metabotropic glutamate receptors were investigated in CA3 pyramidal cells in hippocampal slice cultures of the rat. Earlier experiments showed that selective activation of metabotropic glutamate receptors with low concentrations of an agonist, 1S, 3R-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD), induced an inward current associated with a decrease in membrane conductance and inhibition of the slow calcium-dependent potassium current. These responses were strongly and reversibly reduced by the antagonist, (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 0.5-1 mM). In the presence of antagonists of ionotropic glutamate receptors, stimulation of the afferent mossy fibres evoked postsynaptic responses in CA3 pyramidal cells which paralleled those observed with exogenously applied metabotropic glutamate receptor agonists, i.e. a slow inward current and a reduction of calcium-dependent potassium current. Both responses were greatly reduced by bath-applied MCPG (1 mM). These results show that MCPG acts as an effective antagonist at metabotropic glutamate receptors coupled to potassium conductances in the hippocampus. Furthermore, they confirm that glutamate release from presynaptic terminals can modulate postsynaptic properties by activation of metabotropic glutamate receptors.

  2. Naturally-Occurring Glucosinolates, Glucoraphanin and Glucoerucin, are Antagonists to Aryl Hydrocarbon Receptor as Their Chemopreventive Potency.

    Science.gov (United States)

    Abdull Razis, Ahmad Faizal; Noor, Noramaliza Mohd

    2015-01-01

    As a cytosolic transcription factor, the aryl hydrocarbon (Ah) receptor is involved in several patho- physiological events leading to immunosuppression and cancer; hence antagonists of the Ah receptor may possess chemoprevention properties. It is known to modulate carcinogen-metabolising enzymes, for instance the CYP1 family of cytochromes P450 and quinone reductase, both important in the biotransformation of many chemical carcinogens via regulating phase I and phase II enzyme systems. Utilising chemically-activated luciferase expression (CALUX) assay it was revealed that intact glucosinolates, glucoraphanin and glucoerucin, isolated from Brassica oleracea L. var. acephala sabellica and Eruca sativa ripe seeds, respectively, are such antagonists. Both glucosinolates were poor ligands for the Ah receptor; however, they effectively antagonised activation of the receptor by the avid ligand benzo[a]pyrene. Indeed, intact glucosinolate glucoraphanin was a more potent antagonist to the receptor than glucoerucin. It can be concluded that both glucosinolates effectively act as antagonists for the Ah receptor, and this may contribute to their established chemoprevention potency.

  3. A novel urotensin II receptor antagonist, KR-36996, improved cardiac function and attenuated cardiac hypertrophy in experimental heart failure.

    Science.gov (United States)

    Oh, Kwang-Seok; Lee, Jeong Hyun; Yi, Kyu Yang; Lim, Chae Jo; Park, Byung Kil; Seo, Ho Won; Lee, Byung Ho

    2017-03-15

    Urotensin II and its receptor are thought to be involved in various cardiovascular diseases such as heart failure, pulmonary hypertension and atherosclerosis. Since the regulation of the urotensin II/urotensin II receptor offers a great potential for therapeutic strategies related to the treatment of cardiovascular diseases, the study of selective and potent antagonists for urotensin II receptor is more fascinating. This study was designed to determine the potential therapeutic effects of a newly developed novel urotensin II receptor antagonist, N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl)benzo[b]thiophene-3-carboxamide (KR-36996), in experimental models of heart failure. KR-36996 displayed a high binding affinity (Ki=4.44±0.67nM) and selectivity for urotensin II receptor. In cell-based study, KR-36996 significantly inhibited urotensin II-induced stress fiber formation and cellular hypertrophy in H9c2UT cells. In transverse aortic constriction-induced cardiac hypertrophy model in mice, the daily oral administration of KR-36996 (30mg/kg) for 14 days significantly decreased left ventricular weight by 40% (Preceptor antagonist could efficiently attenuate both cardiac hypertrophy and dysfunction in experimental heart failure. KR-36996 may be useful as an effective urotensin II receptor antagonist for pharmaceutical or clinical applications.

  4. Mercaptoacetate blocks fatty acid-induced GLP-1 secretion in male rats by directly antagonizing GPR40 fatty acid receptors.

    Science.gov (United States)

    Li, Ai-Jun; Wang, Qing; Dinh, Thu T; Simasko, Steve M; Ritter, Sue

    2016-04-15

    Mercaptoacetate (MA) is an orexigenic agent reported to block fatty acid (FA) oxidation. Recently, however, we reported evidence from isolated nodose ganglion neurons that MA antagonizes the G protein-coupled long- and medium-chain FA receptor GPR40. GPR40 mediates FA-induced secretion of the satietogenic incretin peptide glucagon-like peptide 1 (GLP-1), by enteroendocrine L cells, as well as FA-induced enhancement of glucose-stimulated insulin secretion. Our results in cultured nodose neurons suggest that MA would also block GPR40 in enteroendocrine cells controlling GLP-1 secretion. If so, this would suggest an alternative mechanism by which MA increases food intake. We tested the hypothesis that MA blocks FA-induced GLP-1 secretion in vitro using cultured STC-1 cells (a murine enteroendocrine cell line) and in vivo in adult male rats. In vitro, MA blocked the increase in both cytosolic Ca(2+)and GLP-1 release stimulated by FAs and also reduced (but less effectively) the response of STC-1 cells to grifolic acid, a partial agonist of the GPR120 FA receptor. In vivo, MA reduced GLP-1 secretion following olive oil gavage while also increasing glucose and decreasing insulin levels. The carnitine palmatoyltransferase 1 antagonist etomoxir did not alter these responses. Results indicate that MA's actions, including its orexigenic effect, are mediated by GPR40 (and possibly GPR120) receptor antagonism and not by blockade of fat oxidation, as previously believed. Analysis of MA's interaction with GPR40 may facilitate understanding of the multiple functions of this receptor and the manner in which FAs participate in the control of hunger and satiety.

  5. The Administration of Levocabastine, a NTS2 Receptor Antagonist, Modifies Na(+), K(+)-ATPase Properties.

    Science.gov (United States)

    Gutnisky, Alicia; López Ordieres, María Graciela; Rodríguez de Lores Arnaiz, Georgina

    2016-06-01

    Neurotensin behaves as a neuromodulator or as a neurotransmitter interacting with NTS1 and NTS2 receptors. Neurotensin in vitro inhibits synaptosomal membrane Na(+), K(+)-ATPase activity. This effect is prevented by administration of SR 48692 (antagonist for NTS1 receptor). The administration of levocabastine (antagonist for NTS2 receptor) does not prevent Na(+), K(+)-ATPase inhibition by neurotensin when the enzyme is assayed with ATP as substrate. Herein levocabastine effect on Na(+), K(+)-ATPase K(+) site was explored. For this purpose, levocabastine was administered to rats and K(+)-p-nitrophenylphosphatase (K(+)-p-NPPase) activity in synaptosomal membranes and [(3)H]-ouabain binding to cerebral cortex membranes were assayed in the absence (basal) and in the presence of neurotensin. Male Wistar rats were administered with levocabastine (50 μg/kg, i.p., 30 min) or the vehicle (saline solution). Synaptosomal membranes were obtained from cerebral cortex by differential and gradient centrifugation. The activity of K(+)-p-NPPase was determined in media laking or containing ATP plus NaCl. In such phosphorylating condition enzyme behaviour resembles that observed when ATP hydrolyses is recorded. In the absence of ATP plus NaCl, K(+)-p-NPPase activity was similar for levocabastine or vehicle injected (roughly 11 μmole hydrolyzed substrate per mg protein per hour). Such value remained unaltered by the presence of 3.5 × 10(-6) M neurotensin. In the phosphorylating medium, neurotensin decreased (32 %) the enzyme activity in membranes obtained from rats injected with the vehicle but failed to alter those obtained from rats injected with levocabastine. Levocabastine administration enhanced (50 %) basal [(3)H]-ouabain binding to cerebral cortex membranes but failed to modify neurotensin inhibitory effect on this ligand binding. It is concluded that NTS2 receptor blockade modifies the properties of neuronal Na(+), K(+)-ATPase and that neurotensin effect on Na(+), K

  6. Anxiolytic-like effects of mGlu1 and mGlu5 receptor antagonists in rats.

    Science.gov (United States)

    Pietraszek, Małgorzata; Sukhanov, Ilia; Maciejak, Piotr; Szyndler, Janusz; Gravius, Andreas; Wisłowska, Aleksandra; Płaźnik, Adam; Bespalov, Anton Y; Danysz, Wojciech

    2005-05-02

    The purpose of the present study was to compare anxiolytic activity of the metabotropic glutamate receptor 1 (mGlu) antagonist, EMQMCM ((3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate) and the mGlu5 receptor antagonist MTEP ([(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine) and MPEP (2-methyl-6-(phenylethynyl)pyridine) in animal models of anxiety. In the elevated plus maze, diazepam (1 mg/kg), but not the mGlu1 or mGlu5 receptor antagonists induced anxiolytic-like effects. Meanwhile, MTEP (2.5 and 5 mg/kg), EMQMCM (5 mg/kg), and diazepam (2 mg/kg) all significantly inhibited fear potentiated startle. In the contextual fear conditioning test, MTEP (1.25 and 2.5 but not 5 mg/kg) and EMQMCM (0.6 to 5 mg/kg) attenuated freezing responding. In the Geller-Seifter conflict test, MPEP (1 and 3 mg/kg), MTEP (3 mg/kg), chlordiazepoxide (10 and 20 mg/kg) and midazolam (1 mg/kg) all facilitated punished responding, while ECMQCM failed to produce any significant effects up to 3 mg/kg dose. To summarise, the present data further support a significant anxiolytic potential of group I mGlu receptor antagonists, while suggesting the effects of mGlu1 receptor antagonists may depend on the experimental procedure and may be qualitatively different from those of mGlu5 receptor antagonists.

  7. Salvianolic Acid A, as a Novel ETA Receptor Antagonist, Shows Inhibitory Effects on Tumor in Vitro

    Directory of Open Access Journals (Sweden)

    Qiao Zhang

    2016-08-01

    Full Text Available Endothelin-1 (ET-1 autocrine and paracrine signaling modulate cell proliferation of tumor cells by activating its receptors, endothelin A receptor (ETAR and endothelin B receptor (ETBR. Dysregulation of ETAR activation promotes tumor development and progression. The potential of ETAR antagonists and the dual-ETAR and ETBR antagonists as therapeutic approaches are under preclinical and clinical studies. Salvianolic acid A (Sal A is a hydrophilic polyphenolic derivative isolated from Salvia miltiorrhiza Bunge (Danshen, which has been reported as an anti-cancer and cardio-protective herbal medicine. In this study, we demonstrate that Sal A inhibits ETAR activation induced by ET-1 in both recombinant and endogenous ETAR expression cell lines. The IC50 values were determined as 5.7 µM in the HEK293/ETAR cell line and 3.14 µM in HeLa cells, respectively. Furthermore, our results showed that Sal A suppressed cell proliferation and extended the doubling times of multiple cancer cells, including HeLa, DU145, H1975, and A549 cell lines. In addition, Sal A inhibited proliferation of DU145 cell lines stimulated by exogenous ET-1 treatment. Moreover, the cytotoxicity and cardio-toxicity of Sal A were assessed in human umbilical vein endothelial cells (HUVEC and Human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs, which proved that Sal A demonstrates no cytotoxicity or cardiotoxicity. Collectively, our findings indicate that Sal A is a novel anti-cancer candidate through targeting ETAR.

  8. Histamine-2 receptor antagonist famotidine modulates cardiac stem cell characteristics in hypertensive heart disease

    Directory of Open Access Journals (Sweden)

    Sherin Saheera

    2017-10-01

    Full Text Available Background Cardiac stem cells (CSCs play a vital role in cardiac homeostasis. A decrease in the efficiency of cardiac stem cells is speculated in various cardiac abnormalities. The maintenance of a healthy stem cell population is essential for the prevention of adverse cardiac remodeling leading to cardiac failure. Famotidine, a histamine-2 receptor antagonist, is currently used to treat ulcers of the stomach and intestines. In repurposing the use of the drug, reduction of cardiac hypertrophy and improvement in cardiac function of spontaneously hypertensive rats (SHR was reported by our group. Given that stem cells are affected in cardiac pathologies, the effect of histamine-2 receptor antagonism on CSC characteristics was investigated. Methods To examine whether famotidine has a positive effect on CSCs, spontaneously hypertensive rats (SHR treated with the drug were sacrificed; and CSCs isolated from atrial appendages was evaluated. Six-month-old male SHRs were treated with famotidine (30 mg/kg/day for two months. The effect of famotidine treatment on migration, proliferation and survival of CSCs was compared with untreated SHRs and normotensive Wistar rats. Results Functional efficiency of CSCs from SHR was compromised relative to that in Wistar rat. Famotidine increased the migration and proliferation potential, along with retention of stemness of CSCs in treated SHRs. Cellular senescence and oxidative stress were also reduced. The expression of H2R was unaffected by the treatment. Discussion As anticipated, CSCs from SHRs were functionally impaired. Stem cell attributes of famotidine-treated SHRs was comparable to that of Wistar rats. Therefore, in addition to being cardioprotective, the histamine 2 receptor antagonist modulated cardiac stem cells characteristics. Restoration of stem cell efficiency by famotidine is possibly mediated by reduction of oxidative stress as the expression of H2R was unaffected by the treatment. Maintenance of

  9. GabaB receptors activation in the NTS blocks the glycemic responses induced by carotid body receptor stimulation.

    Science.gov (United States)

    Lemus, Mónica; Montero, Sergio; Cadenas, José Luis; Lara, José Jesús; Tejeda-Chávez, Héctor Rafael; Alvarez-Buylla, Ramón; de Alvarez-Buylla, Elena Roces

    2008-08-18

    The carotid body receptors participate in glucose regulation sensing glucose levels in blood entering the cephalic circulation. The carotid body receptors information, is initially processed within the nucleus tractus solitarius (NTS) and elicits changes in circulating glucose and brain glucose uptake. Previous work has shown that gamma-aminobutyric acid (GABA) in NTS modulates respiratory reflexes, but the role of GABA within NTS in glucose regulation remains unknown. Here we show that GABA(B) receptor agonist (baclofen) or antagonists (phaclofen and CGP55845A) locally injected into NTS modified arterial glucose levels and brain glucose retention. Control injections outside NTS did not elicit these responses. In contrast, GABA(A) agonist and antagonist (muscimol or bicuculline) produced no significant changes in blood glucose levels. When these GABAergic drugs were applied before carotid body receptors stimulation, again, only GABA(B) agonist or antagonist significantly affected glycemic responses; baclofen microinjection significantly reduced the hyperglycemic response and brain glucose retention observed after carotid body receptors stimulation, while phaclofen produced the opposite effect, increasing significantly hyperglycemia and brain glucose retention. These results indicate that activation of GABA(B), but not GABA(A), receptors in the NTS modulates the glycemic responses after anoxic stimulation of the carotid body receptors, and suggest the presence of a tonic inhibitory mechanism in the NTS to avoid hyperglycemia.

  10. Impaired effect of activation of rat hippocampal 5-HT7 receptors, induced by treatment with the 5-HT7 receptor antagonist SB 269970.

    Science.gov (United States)

    Kusek, M; Sowa, J; Tokarski, K; Hess, G

    2015-04-01

    Effects of the 5-HT(7) receptor antagonist SB 269970, administered for 14 days (1.25 mg/kg), were studied in ex vivo slices of rat hippocampus. To activate the 5-HT(7) receptor, 5-carboxamidotryptamine (5-CT, 200 nM) was applied in the presence of WAY 100635 (2 μM), a 5-HT(1A) receptor antagonist. In contrast to control preparations, no 5-HT(7) receptor-mediated increase in excitability nor depolarization and an increase in the input resistance of CA1 and CA3 pyramidal neurons were present in slices prepared from rats treated with SB 269970. The treatment also abolished the stimulatory effect of 5-HT(7) receptor activation on spontaneous excitatory postsynaptic currents recorded from CA1 stratum radiatum/lacunosum-moleculare interneurons. These data demonstrate that repeated administration of SB 269970 impairs the reactivity of the CA1 hippocampal neuronal network to 5-HT(7) receptor activation.

  11. Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors

    DEFF Research Database (Denmark)

    Venskutonyte, Raminta; Frydenvang, Karla; Valadés, Elena Antón

    2012-01-01

    . A new series of phenylalanine derivatives that target iGluRs was reported to bind AMPA receptors. Herein we report our studies of these compounds at the kainate receptors GluK1-3. Several compounds bind with micromolar affinity at GluK1 and GluK3, but do not bind GluK2. The crystal structure of the most...... potent compound in the ligand binding domain of GluK1 revealed different modes of binding to GluK1 and GluA2, due primarily to residues Ser741 (GluK1) and Met729 (GluA2). The compound was shown to be slightly more potent at GluK1 than at AMPA receptors and to induce a domain closure similar...

  12. Effect of the selective vasopressin V2 receptor antagonists in hepatic cirrhosis patients with ascites: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Shao-hui TANG

    2013-07-01

    Full Text Available Objective To evaluate the efficacy and safety of selective vasopressin V2 receptor antagonists in the treatment of hepatic cirrhosis patients with ascites. Methods PubMed, EMBASE, Web of Science, The Cochrane Central Register of Controlled Trials, Database for Chinese Technical Periodical (VIP, Chinese Journal Full-Text Database (CNKI, and Wan Fang Digital Journal Full-text Database were retrieved to collect clinical randomized controlled trials of hepatic cirrhosis with ascites treated by selective vasopressin V2 receptor antagonists. Meta analysis was performed by using Review Manager 5.0. Results Nine randomized controlled trials including 1884 patients met the inclusion criteria. Meta-analysis showed that: 1 The selective vasopressin V2 receptor antagonists were associated with a significant reduction in body weight compared with placebo (WMD=–1.98kg, 95%CI:–3.24-–0.72kg, P=0.002. Treatment with selective vasopressin V2 receptor antagonists was associated with an improvement of low serum sodium concentration compared to placebo (WMD=3.74mmol/L, 95%CI: 0.91-6.58mmol/L, P=0.01. The percentage of patients with worsening ascites was higher in the group of patients treated with placebo (RR=0.51, 95%CI: 0.34-0.77, P=0.001. 2 The amplitude of increased urine volume was obviously higher in selective vasopressin V2 receptor antagonists group than in placebo group (WMD=1437.65ml, 95%CI: 649.01-2226.30ml, P=0.0004. The difference of serum creatinine in the selective vasopressin V2 receptor antagonists group was not statistically significant compared with the control group (WMD=–3.49μmol/L, 95%CI: –12.54¬5.56μmol/L, P=0.45. 3 There was no statistical significance between the two groups in the heart rate, systolic pressure, diastolic pressure and mortality (P>0.05. The rate of other adverse reactions was higher in the selective vasopressin V2 receptor antagonists group compared with that of placebo group (P=0.003. Conclusion

  13. Synthesis and evaluation of carbamate and aryl ether substituted pyrazinones as corticotropin releasing factor-1 (CRF₁) receptor antagonists.

    Science.gov (United States)

    Ahuja, Vijay T; Hartz, Richard A; Molski, Thaddeus F; Mattson, Gail K; Lentz, Kimberley A; Grace, James E; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E

    2016-05-01

    A series of pyrazinone-based compounds incorporating either carbamate or aryl ether groups was synthesized and evaluated as corticotropin-releasing factor-1 (CRF1) receptor antagonists. Structure-activity relationship studies led to the identification of highly potent CRF1 receptor antagonists 14a (IC50=0.74 nM) and 14b (IC50=1.9 nM). The synthesis, structure-activity relationships and in vitro metabolic stability properties of compounds in this series will be described. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

    OpenAIRE

    Helmy, Adel; Guilfoyle, Mathew R.; Carpenter, Keri LH; Pickard, John D.; Menon, David K.; Hutchinson, Peter J.

    2014-01-01

    Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in se...

  15. The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

    Science.gov (United States)

    Lichtenfels, Martina; Dornelles, Arethuza da Silva; Petry, Fernanda Dos Santos; Blank, Martina; de Farias, Caroline Brunetto; Roesler, Rafael; Schwartsmann, Gilberto

    2017-09-02

    Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

  16. Block of GABA(A) receptor ion channel by penicillin: electrophysiological and modeling insights toward the mechanism.

    Science.gov (United States)

    Rossokhin, Alexey V; Sharonova, Irina N; Bukanova, Julia V; Kolbaev, Sergey N; Skrebitsky, Vladimir G

    2014-11-01

    GABA(A) receptors (GABA(A)R) mainly mediate fast inhibitory neurotransmission in the central nervous system. Different classes of modulators target GABA(A)R properties. Penicillin G (PNG) belongs to the class of noncompetitive antagonists blocking the open GABA(A)R and is a prototype of β-lactam antibiotics. In this study, we combined electrophysiological and modeling approaches to investigate the peculiarities of PNG blockade of GABA-activated currents recorded from isolated rat Purkinje cells and to predict the PNG binding site. Whole-cell patch-сlamp recording and fast application system was used in the electrophysiological experiments. PNG block developed after channel activation and increased with membrane depolarization suggesting that the ligand binds within the open channel pore. PNG blocked stationary component of GABA-activated currents in a concentration-dependent manner with IC50 value of 1.12mM at -70mV. The termination of GABA and PNG co-application was followed by a transient tail current. Protection of the tail current from bicuculline block and dependence of its kinetic parameters on agonist affinity suggest that PNG acts as a sequential open channel blocker that prevents agonist dissociation while the channel remains blocked. We built the GABA(A)R models based on nAChR and GLIC structures and performed an unbiased systematic search of the PNG binding site. Monte-Carlo energy minimization was used to find the lowest energy binding modes. We have shown that PNG binds close to the intracellular vestibule. In both models the maximum contribution to the energy of ligand-receptor interactions revealed residues located on the level of 2', 6' and 9' rings formed by a bundle of M2 transmembrane segments, indicating that these residues most likely participate in PNG binding. The predicted structural models support the described mechanism of PNG block.

  17. Urinary responses to acute moxonidine are inhibited by natriuretic peptide receptor antagonist.

    Science.gov (United States)

    El-Ayoubi, Rouwayda; Menaouar, Ahmed; Gutkowska, Jolanta; Mukaddam-Daher, Suhayla

    2005-05-01

    We have previously shown that acute intravenous injections of moxonidine and clonidine increase plasma atrial natriuretic peptide (ANP), a vasodilator, diuretic and natriuretic hormone. We hypothesized that moxonidine stimulates the release of ANP, which would act on its renal receptors to cause diuresis and natriuresis, and these effects may be altered in hypertension. Moxonidine (0, 10, 50, 100 or 150 microg in 300 microl saline) and clonidine (0, 1, 5 or 10 microg in 300 microl saline) injected intravenously in conscious normally hydrated normotensive Sprague-Dawley rats (SD, approximately 200 g) and 12-14-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) dose-dependently stimulated diuresis, natriuresis, kaliuresis and cGMP excretion, with these effects being more pronounced during the first hour post-injection. The actions of 5 microg clonidine and 50 microg moxonidine were inhibited by yohimbine, an alpha2-adrenoceptor antagonist, and efaroxan, an imidazoline I1-receptor antagonist. Moxonidine (100 microg) stimulated (P<0.01) diuresis in SHR (0.21+/-0.04 vs 1.16+/-0.06 ml h(-1) 100 g(-1)), SD (0.42+/-0.06 vs 1.56+/-0.19 ml h(-1) 100 g(-1)) and WKY (0.12+/-0.04 vs 1.44+/-0.21 ml h(-1) 100 g(-1)). Moxonidine-stimulated urine output was lower in SHR than in SD and WKY. Moxonidine-stimulated sodium and potassium excretions were lower in SHR than in SD, but not WKY, demonstrating an influence of strain but not of pressure. Pretreatment with the natriuretic peptide antagonist anantin (5 or 10 microg) resulted in dose-dependent inhibition of moxonidine-stimulated urinary actions. Anantin (10 microg) inhibited (P<0.01) urine output to 0.38+/-0.06, 0.12+/-0.01, and 0.16+/-0.04 ml h(-1) 100 g(-1) in SD, WKY, and SHR, respectively. Moxonidine increased (P<0.01) plasma ANP in SD (417+/-58 vs 1021+/-112 pg ml(-1)) and WKY (309+/-59 vs 1433+/-187 pg ml(-1)), and in SHR (853+/-96 vs 1879+/-229 pg ml(-1)). These results demonstrate that natriuretic

  18. Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Poulton, Emma Jane [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Levy, Lisa [Public Health Sciences Division, Fred Hutchinson Cancer Research Center (United States); Lampe, Johanna W. [Center for Ecogenetics and Environmental Health, University of Washington (United States); Public Health Sciences Division, Fred Hutchinson Cancer Research Center (United States); Shen, Danny D. [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States); Tracy, Julia [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Shuhart, Margaret C. [Division of Gastroenterology, Department of Medicine (United States); Thummel, Kenneth E. [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States); Eaton, David L., E-mail: deaton@uw.edu [Center for Ecogenetics and Environmental Health, University of Washington (United States); Department of Environmental and Occupational Health Sciences, University of Washington (United States); Department of Pharmaceutics, University of Washington (United States)

    2013-01-01

    Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was given alone for 7 days in arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ► The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ► SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ► SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ► Humanized PXR

  19. The angiotensin II type 1 receptor antagonist Losartan binds and activates bradykinin B2 receptor signaling

    DEFF Research Database (Denmark)

    Bonde, Marie Mi; Olsen, Kristine Boisen; Erikstrup, Niels;

    2011-01-01

    The angiotensin II type 1 receptor (AT1R) blocker (ARB) Losartan has cardioprotective effects during ischemia-reperfusion injury and inhibits reperfusion arrhythmias -effects that go beyond the benefits of lowering blood pressure. The renin-angiotensin and kallikrein-kinin systems are intricately...

  20. Bone Morphogenetic Protein Type I Receptor Antagonists Decrease Growth and Induce Cell Death of Lung Cancer Cell Lines

    Science.gov (United States)

    Langenfeld, Elaine; Hong, Charles C.; Lanke, Gandhi; Langenfeld, John

    2013-01-01

    Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade. PMID:23593444

  1. Critical Evaluation of P2X7 Receptor Antagonists in Selected Seizure Models

    Science.gov (United States)

    Fischer, Wolfgang; Franke, Heike; Krügel, Ute; Müller, Heiko; Dinkel, Klaus; Lord, Brian; Letavic, Michael A.; Henshall, David C.; Engel, Tobias

    2016-01-01

    The ATP-gated P2X7 receptor (P2X7R) is a non-selective cation channel which senses high extracellular ATP concentrations and has been suggested as a target for the treatment of neuroinflammation and neurodegenerative diseases. The use of P2X7R antagonists may therefore be a viable approach for treating CNS pathologies, including epileptic disorders. Recent studies showed anticonvulsant potential of P2X7R antagonists in certain animal models. To extend this work, we tested three CNS-permeable P2X7R blocker (Brilliant Blue G, AFC-5128, JNJ-47965567) and a natural compound derivative (tanshinone IIA sulfonate) in four well-characterized animal seizure models. In the maximal electroshock seizure threshold test and the pentylenetetrazol (PTZ) seizure threshold test in mice, none of the four compounds demonstrated anticonvulsant effects when given alone. Notably, in combination with carbamazepine, both AFC-5128 and JNJ-47965567 increased the threshold in the maximal electroshock seizure test. In the PTZ-kindling model in rats, useful for testing antiepileptogenic activities, Brilliant Blue G and tanshinone exhibited a moderate retarding effect, whereas the potent P2X7R blocker AFC-5128 and JNJ-47965567 showed a significant and long-lasting delay in kindling development. In fully kindled rats, the investigated compounds revealed modest effects to reduce the mean seizure stage. Furthermore, AFC-5128- and JNJ-47965567-treated animals displayed strongly reduced Iba 1 and GFAP immunoreactivity in the hippocampal CA3 region. In summary, our results show that P2X7R antagonists possess no remarkable anticonvulsant effects in the used acute screening tests, but can attenuate chemically-induced kindling. Further studies would be of interest to support the concept that P2X7R signalling plays a crucial role in the pathogenesis of epileptic disorders. PMID:27281030

  2. Effect of α₇ nicotinic acetylcholine receptor agonists and antagonists on motor function in mice.

    Science.gov (United States)

    Welch, Kevin D; Pfister, James A; Lima, Flavia G; Green, Benedict T; Gardner, Dale R

    2013-02-01

    Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels found throughout the body, and serve to mediate diverse physiological functions. Muscle-type nAChRs located in the motor endplate region of muscle fibers play an integral role in muscle contraction and thus motor function. The toxicity and teratogenicity of many plants (which results in millions of dollars in losses annually to the livestock industry) are due to various toxins that bind to nAChRs including deltaline and methyllycaconitine (MLA) from larkspur (Delphinium) species, and nicotine and anabasine from tobacco (Nicotiana) species. The primary result of the actions of these alkaloids at nAChRs is neuromuscular paralysis and respiratory failure. The objective of this study was to further characterize the motor coordination deficiencies that occur upon exposure to a non-lethal dose of nAChR antagonists MLA and deltaline as well as nAChR agonists nicotine and anabasine. We evaluated the effect of nAChR agonists and antagonists on the motor function and coordination in mice using a balance beam, grip strength meter, rotarod, open field analysis and tremor monitor. These analyses demonstrated that within seconds after treatment the mice had significant loss of motor function and coordination that lasted up to 1 min, followed by a short period of quiescence. Recovery to normal muscle coordination was rapid, typically within approximately 10 min post-dosing. However, mice treated with the nAChR agonist nicotine and anabasine required a slightly longer time to recover some aspects of normal muscle function in comparison to mice treated with the nAChR antagonist MLA or deltaline.

  3. The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model.

    Science.gov (United States)

    Smith, K A; Fisher, R S

    1996-08-12

    Slow IPSPs, which are believed to be involved in generation of the wave of spike-wave epileptiform discharges, are mediated by the GABAB receptor. We therefore examined the effect of the GABAB antagonist, Ciba Geigy Product, CGP-35348, in the cholesterol synthesis inhibitor model of absence epilepsy in rat. Rats received Ayerst-9944 (AY-9944), from 6-45 mg i.p. in the first few weeks of life. By 2 months after AY-9944 administration these rats exhibited recurrent spike-waves and behavioral arrests. In 10 such animals CGP-35348 was administered intraperitoneally in doses of 0 (vehicle), 10, 25 or 100 mg/kg. EEG recordings were obtained via previously implanted bone screws. Technologists blinded to treatment group counted spike-waves over a 4 h period post-injection. The average number of spike-wave burst seconds per 4 h of recording for all dosages and times was 52.4 +/- 81.4 (mean +/- S.D.) s. Mean burst times (seconds) were vehicle = 93.5 +/- 106.5; 10 mg/kg = 69.9 +/- 79.7; 25 mg/kg = 30.8 +/- 46.9; 100 mg/kg = 15.2 +/- 54, a mean 84% reduction at 100 mg/kg (ANOVA regression significant at 0.0001). Spike-waves were suppressed for at least 4 h after injection of CGP-35348. These findings supplement similar findings in other absence models, and support a potential role for GABAB antagonists in treatment of absence seizures.

  4. A Selective Nociceptin Receptor Antagonist to Treat Depression: Evidence from Preclinical and Clinical Studies.

    Science.gov (United States)

    Post, Anke; Smart, Trevor S; Krikke-Workel, Judith; Dawson, Gerard R; Harmer, Catherine J; Browning, Michael; Jackson, Kimberley; Kakar, Rishi; Mohs, Richard; Statnick, Michael; Wafford, Keith; McCarthy, Andrew; Barth, Vanessa; Witkin, Jeffrey M

    2016-06-01

    Nociceptin/Orphanin FQ (N/OFQ) is an endogenous ligand of the N/OFQ peptide (NOP) receptor, which is a G protein-coupled receptor in brain regions associated with mood disorders. We used a novel, potent, and selective orally bioavailable antagonist, LY2940094, to test the hypothesis that blockade of NOP receptors would induce antidepressant effects. In this study we demonstrate that targeting NOP receptors with LY2940094 translates to antidepressant-like effects in rodent models and, importantly, to antidepressant efficacy in patients with major depressive disorder (MDD). The proof-of-concept study (POC) was an 8-week, double-blind, placebo-controlled trial that evaluated LY2940094 as a novel oral medication for the treatment of patients with MDD. Once daily oral dosing of LY2940094 at 40 mg for 8 weeks vs placebo provided some evidence for an antidepressant effect based on the change from baseline to week 8 in the GRID-Hamilton Depression Rating Scale-17 item total score, although the predefined POC efficacy criterion (probability of LY2940094 being better than placebo⩾88%) was not met (82.9%). LY2940094 also had an early effect on the processing of emotional stimuli at Week 1 as shown by an increased recognition of positive relative to negative facial expressions in an emotional test battery. LY2940094 was safe and well tolerated. Overall, these are the first human data providing evidence that the blockade of NOP receptor signaling represents a promising strategy for the treatment of MDD.

  5. Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M.; Sunahara, Roger K.; Pardo, Leonardo; Weis, William I.; Kobilka, Brian K.; Granier, Sébastien (Michigan-Med); (Stanford-MED); (UAB, Spain)

    2012-06-27

    Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the {mu}-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

  6. The muscle relaxant thiocolchicoside is an antagonist of GABAA receptor function in the central nervous system.

    Science.gov (United States)

    Carta, Mario; Murru, Luca; Botta, Paolo; Talani, Giuseppe; Sechi, GianPietro; De Riu, PierLuigi; Sanna, Enrico; Biggio, Giovanni

    2006-09-01

    Thiocolchicoside (TCC) is used clinically for its muscle relaxant, anti-inflammatory, and analgesic properties, and it has been shown to interact with gamma-aminobutyric acid (GABA) type A receptors (GABAARs) and strychnine-sensitive glycine receptors in the rat central nervous system. In contrast to a proposed agonistic action at these two types of inhibitory receptors, pharmacological evidence has shown that, under certain conditions, TCC manifests convulsant activity in animals and humans. We now show that the phasic and tonic GABAAR-mediated currents recorded from Purkinje cells and granule neurons, respectively, in parasagittal cerebellar slices from adult male rats were inhibited by TCC in a concentration-dependent manner. The median inhibitory concentrations of TCC for these effects were approximately 0.15 and approximately 0.9 microM, respectively. TCC did not potentiate GABABR-mediated currents in hippocampal slices, suggesting that its muscle relaxant action is not mediated by GABABRs. Intraperitoneal injection of TCC in rats either alone or in combination with negative modulators of GABAergic transmission revealed convulsant and proconvulsant actions of this drug. Our data, consistent with clinical observations of the epileptogenic effect of this compound, suggest that TCC is a potent competitive antagonist of GABAAR function.

  7. Use of prolactin receptor antagonist to better understand prolactin regulation of pituitary homeostasis.

    Science.gov (United States)

    Ferraris, Jimena; Bernichtein, Sophie; Pisera, Daniel; Goffin, Vincent

    2013-01-01

    The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level. © 2013 S. Karger AG, Basel.

  8. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium.

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2012-02-01

    BACKGROUND: Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. RESULTS: Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. CONCLUSION: Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.

  9. Molecular determinants responsible for sedative and non-sedative properties of histamine H₁-receptor antagonists.

    Science.gov (United States)

    Uesawa, Yoshihiro; Hishinuma, Shigeru; Shoji, Masaru

    2014-01-01

    There is argument whether non-sedative properties of histamine H1-receptor antagonists (antihistamines) are determined by their active extrusions from the brain via P-glycoprotein or their restricted penetration through the blood-brain barrier. We have reported that sedative and non-sedative antihistamines can be well discriminated by measuring changes in their binding to H1 receptors upon receptor internalization in intact cells, which depends on their membrane-penetrating ability. In this study, molecular determinants responsible for sedative and non-sedative properties of antihistamines were evaluated by quantitative structure-activity relationship (QSAR) analyses. Multiple regression analyses were applied to construct a QSAR model, taking internalization-mediated changes in the binding of antihistamines as objective variables and their structural descriptors as explanatory variables. The multiple regression model was successfully constructed with two explanatory variables, i.e., lipophilicity of the compounds at physiological pH (logD) and mean information content on the distance degree equality (IDDE) (r(2) = 0.753). The constructed model discriminated between sedative and non-sedative antihistamines with 94% accuracy for external validation. These results suggest that logD and IDDE concerning lipophilicity and molecular shapes of compounds, respectively, predominantly determine the membrane-penetrating ability of antihistamines for their side effects on the central nervous system.

  10. A novel thromboxane receptor antagonist, nstpbp5185, inhibits platelet aggregation and thrombus formation in animal models.

    Science.gov (United States)

    Huang, Shiu-Wen; Kuo, Heng-Lan; Hsu, Ming-Tsung; Tseng, Yufeng Jane; Lin, Shu-Wha; Kuo, Sheng-Chu; Peng, Hui-Chin; Lien, Jin-Cherng; Huang, Tur-Fu

    2016-08-01

    A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thromaboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 µM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective anti-thrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.

  11. Gene expression profiling of the androgen receptor antagonists flutamide and vinclozolin in zebrafish (Danio rerio) gonads

    Energy Technology Data Exchange (ETDEWEB)

    Martinovic-Weigelt, Dalma, E-mail: dalma@stthomas.edu [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States); University of St. Thomas, 2115 Summit Ave, Saint Paul, MN 55105 (United States); Wang Ronglin [US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, 26W. Martin Luther King Dr., Cincinnati, OH 45268 (United States); Villeneuve, Daniel L. [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States); Bencic, David C.; Lazorchak, Jim [US Environmental Protection Agency, Office of Research and Development, National Exposure Research Laboratory, Ecological Exposure Research Division, 26W. Martin Luther King Dr., Cincinnati, OH 45268 (United States); Ankley, Gerald T. [US Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, Mid-Continent Ecology Division, 6201 Congdon Blvd., Duluth, MN 55804 (United States)

    2011-01-25

    The studies presented in this manuscript focus on characterization of transcriptomic responses to anti-androgens in zebrafish (Danio rerio). Research on the effects of anti-androgens in fish has been characterized by a heavy reliance on apical endpoints, and molecular mechanisms of action (MOA) of anti-androgens remain poorly elucidated. In the present study, we examined effects of a short term exposure (24-96 h) to the androgen receptor antagonists flutamide (FLU) and vinclozolin (VZ) on gene expression in gonads of sexually mature zebrafish, using commercially available zebrafish oligonucleotide microarrays (4 x 44 K platform). We found that VZ and FLU potentially impact reproductive processes via multiple pathways related to steroidogenesis, spermatogenesis, and fertilization. Observed changes in gene expression often were shared by VZ and FLU, as demonstrated by overlap in differentially-expressed genes and enrichment of several common key pathways including: (1) integrin and actin signaling, (2) nuclear receptor 5A1 signaling, (3) fibroblast growth factor receptor signaling, (4) polyamine synthesis, and (5) androgen synthesis. This information should prove useful to elucidating specific mechanisms of reproductive effects of anti-androgens in fish, as well as developing biomarkers for this important class of endocrine-active chemicals.

  12. High-throughput screening of novel antagonists on melanin-concentrat-ing hormone receptor-1

    Institute of Scientific and Technical Information of China (English)

    Jian-hua YAN; Qun-yi LI; Jean A BOUTIN; M Pierre RENARD; Yi-xiang DING; Xiao-jiang HAO; Wei-min ZHAO; Ming-wei WANG

    2008-01-01

    Aim: To find new antagonists on human melanin-concentrating hormone recep-tor- 1 (MCHR-1) through high-throughput screening (HTS) of a diverse com-pound library. Methods: MCHR-1, [3H]SNAP7941, and FlashBlue G-protein-coupled receptor beads were used to measure the receptor-binding activities of various compounds based on scintillation proximity assay (SPA) technology. The guanosine 5' (γ-[35S]thio) triphosphate ([35S]GTPγS) binding assay was sub-sequently applied to functionally characterize the "hits" identified by the HTS campaign. Results: Of the 48 240 compounds screened with the SPA method, 12 hits were confirmed to possess MCHR-1 binding activities, 8 were function-ally studied subsequently with the [35S]GTPγS binding assay, and only 1 com-pound (NC 127816) displayed moderate human MCHR- 1 binding affinity (Ki=115.7 nmol/L) and relatively potent antagonism (KB=23.8 nmol/L). This compound shares a novel scaffold (1-ethoxy-2H-2-aza-1-phospha-naphthalene 1-oxide) with 3 other analogs in the group. Conclusion: Considering the marked difference in molecular shape and electrostatic status between NC127816 and the structures reported elsewhere, we anticipate that its derivatives may repre-sent a new class of potent MCHR-1 modulators.

  13. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium

    LENUS (Irish Health Repository)

    Dooley, Ruth

    2011-08-22

    Abstract Background Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Results Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Conclusion Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.

  14. Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

    Directory of Open Access Journals (Sweden)

    Kelly Teske

    2014-04-01

    Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

  15. Pharmacologic Targets and Prototype Therapeutics in the Kallikrein-Kinin System: Bradykinin Receptor Agonists or Antagonists

    Directory of Open Access Journals (Sweden)

    J. N. Sharma

    2006-01-01

    Full Text Available The kallikrein-kinin system (KKS is a complex system produced in various organs. This system includes kininogen (precursor for kinin, kallikreins, and pharmacologically active bradykinin (BK, which is considered to be proinflammatory and/or cardioprotective. It is a proinflammatory polypeptide that is involved in many pathological conditions and can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles, as well as cell proliferation. On the other hand, it has been shown that BK has cardioprotective effects, as all components of KKS are located in the cardiac muscles. Numerous observations have indicated that decreased activity of this system may lead to cardiovascular diseases, such as hypertension, cardiac failure, and myocardial infarction. BK acts on two receptors, B1 and B2, which are linked physiologically through their natural stimuli and their common participation in a variety of inflammatory responses. Recently, numerous BK antagonists have been developed in order to treat several diseases that are due to excessive BK formation. Although BK has many beneficial effects, it has been recognized to have some undesirable effects that can be reversed with BK antagonists. In addition, products of this system have multiple interactions with other important metabolic pathways, such as the renin-angiotensin system.

  16. Development of potent selective competitive-antagonists of the melanocortin type 2 receptor.

    Science.gov (United States)

    Bouw, Elise; Huisman, Martin; Neggers, Sebastian J C M M; Themmen, Axel P N; van der Lely, A J; Delhanty, Patric J D

    2014-08-25

    Cushing's disease, a hypercortisolemic state induced by an ACTH overexpressing pituitary adenoma, causes increased morbidity and mortality. Selective antagonism of the melanocortin type 2 receptor (MC2R) may be a novel treatment modality. Five structurally related peptides with modified HFRW sites but intact putative MC2R binding sites were tested for antagonistic activity at MC1R, MC2R/MRAP, MC3R, MC4R and MC5R. Two of these peptides (GPS1573 and GPS1574) dose-dependently antagonized ACTH-stimulated MC2R activity (IC50s of 66±23 nM and 260±1 nM, respectively). GPS1573 and 1574 suppressed the Rmax but not EC50 of ACTH on MC2R, indicating non-competitive antagonism. These peptides did not antagonize α-MSH stimulation of MC1R and antagonized MC3, 4 and 5R at markedly lower potency. GP1573 and GPS1574 antagonize MC4R with IC50s of 950 nM and 3.7 μM, respectively. In conclusion, two peptide antagonists were developed with selectivity for MC2R, forming a platform for development of a medical treatment for Cushing's disease.

  17. Pyrazole antagonists of the CB1 receptor with reduced brain penetration.

    Science.gov (United States)

    Fulp, Alan; Zhang, Yanan; Bortoff, Katherine; Seltzman, Herbert; Snyder, Rodney; Wiethe, Robert; Amato, George; Maitra, Rangan

    2016-03-01

    Type 1 cannabinoid receptor (CB1) antagonists might be useful for treating obesity, liver disease, metabolic syndrome, and dyslipidemias. Unfortunately, inhibition of CB1 in the central nervous system (CNS) produces adverse effects, including depression, anxiety and suicidal ideation in some patients, which led to withdrawal of the pyrazole inverse agonist rimonabant (SR141716A) from European markets. Efforts are underway to produce peripherally selective CB1 antagonists to circumvent CNS-associated adverse effects. In this study, novel analogs of rimonabant (1) were explored in which the 1-aminopiperidine group was switched to a 4-aminopiperidine, attached at the 4-amino position (5). The piperidine nitrogen was functionalized with carbamates, amides, and sulfonamides, providing compounds that are potent inverse agonists of hCB1 with good selectivity for hCB1 over hCB2. Select compounds were further studied using in vitro models of brain penetration, oral absorption and metabolic stability. Several compounds were identified with predicted minimal brain penetration and good metabolic stability. In vivo pharmacokinetic testing revealed that inverse agonist 8c is orally bioavailable and has vastly reduced brain penetration compared to rimonabant.

  18. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  19. Histamine and histamine type-2 receptor antagonists in psoriasis. Mechanisms and speculations

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1991-01-01

    The findings that the immunosuppressant cyclosporine A (CsA) improves psoriasis raise the possibility that cellular immune processes may play a major role in the pathogenesis of this disease. It is broadly agreed that histamine released by mast cells is one of the molecules involved...... in the pathogenesis. This is supported by the findings that CsA and methotrexate (Mxt) reduce formation and release of histamine. However, the well known side-effects of CsA and Mxt may argue potential use of other agents acting on formation and action of histamine. Such agents may be the histamine-2 receptor...... antagonists, previously reported to have a clinical effect on psoriasis. But randomised short-term studies have disclosed that these drugs have no beneficial or even an aggravating effect on the disease. This article reports on recent findings of improvement in psoriasis using high doses of the histamine-2...

  20. The crystal structure of a bimorphinan with highly selective kappa opioid receptor antagonist activity

    Science.gov (United States)

    Urbańczyk-Lipkowska, Zofia; Etter, Margaret C.; Lipkowski, Andrzej W.; Portoghese, Philip S.

    1987-07-01

    The crystal structure of the dihydrobromide heptahydrate of nor-binaltorphimine (17, 17'-bis(cyclopropylmethyl)-6,6',7,7'-tetrahydro-4,5α: 4',5'α-diepoxy-6,6'-imino[7,7' bimorphinan]-3,3',14,14'-tetraol)is presented. This structure is the first reported structure of a rigid bivalent opioid ligand. Two morphinan pharmacophores are connected by a rigid spacer, the pyrrole ring. The nor-binaltorphimine structure itself shows unique, high selectivity as a kappa opioid receptor antagonist. Crystal data: P3 2, Z = 3, a = b = 20.223 (4), c = 9.541(7) Å, α = β = 90°, γ = 120°; R = 0.079 (1765 reflections, Fobs > 1σ( F)).

  1. Kinin Receptor Antagonists as Potential Neuroprotective Agents in Central Nervous System Injury

    Directory of Open Access Journals (Sweden)

    Anna V Leonard

    2010-09-01

    Full Text Available Injury to the central nervous system initiates complex physiological, cellular and molecular processes that can result in neuronal cell death. Of interest to this review is the activation of the kinin family of neuropeptides, in particular bradykinin and substance P. These neuropeptides are known to have a potent pro-inflammatory role and can initiate neurogenic inflammation resulting in vasodilation, plasma extravasation and the subsequent development of edema. As inflammation and edema play an integral role in the progressive secondary injury that causes neurological deficits, this review critically examines kinin receptor antagonists as a potential neuroprotective intervention for acute brain injury, and more specifically, traumatic brain and spinal cord injury and stroke.

  2. 4-(Phenylsulfonyl)piperidines: novel, selective, and bioavailable 5-HT(2A) receptor antagonists.

    Science.gov (United States)

    Fletcher, Stephen R; Burkamp, Frank; Blurton, Peter; Cheng, Susan K F; Clarkson, Robert; O'Connor, Desmond; Spinks, Daniel; Tudge, Matthew; van Niel, Monique B; Patel, Smita; Chapman, Kerry; Marwood, Rose; Shepheard, Sara; Bentley, Graham; Cook, Gina P; Bristow, Linda J; Castro, Jose L; Hutson, Peter H; MacLeod, Angus M

    2002-01-17

    On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.

  3. Fesoterodine: a novel muscarinic receptor antagonist for the treatment of overactive bladder syndrome.

    Science.gov (United States)

    Michel, Martin C

    2008-07-01

    Fesoterodine is a newly approved drug for the treatment of overactive bladder syndrome. The aim of this study was to review the preclinical and clinical data on fesoterodine. The study involved a search of the Medline database and the proceedings volumes of urological congresses. Fesoterodine functions as an orally active prodrug that is converted to the active metabolite 5-hydroxymethyltolterodine by non-specific esterases. 5-Hydroxymethyltolterodine is a muscarinic receptor antagonist. Fesoterodine is primarily eliminated as inactive metabolites along with significant renal excretion as the unchanged active metabolite 5-hydroxymethyltolterodine. Fesoterodine is indicated for use at doses of 4 and 8 mg once daily. In clinical studies both doses of fesoterodine were consistently superior to placebo in improving the symptoms of overactive bladder syndrome, with 8 mg/day having significantly greater effects than 4 mg/day.

  4. Interleukin-1B and Interleukin-1 Receptor Antagonist in Patients with Helicobacter pylori Associated Diseases

    Directory of Open Access Journals (Sweden)

    Elizaveta S. Ageeva, PhD

    2012-06-01

    Full Text Available The ethnic people of the Republic of Khakassia (the Khakas with ulcer disease show a significant T-cell activation and humoral immune response when compared with the Europoids. The reasons for such differences could be due to certain ethno-specific allelic variants of the interleukins, which considerably change the degree of cytokine expression. The aim was to study the peculiarities of the association of the interleukin-1 (IL-1 gene polymorphisms and interleukin-1 receptor antagonist (IL-1Ra. Patients with chronic gastritis and ulcer disease were examined using the restriction analysis method. The most wide-spread allelic variants among the Khakas were discovered to be С�� IL-1β and R4R4 IL-1Ra. In this study, we suggest the necessity to define the population’s risk and the protective genotypes that promote Helicobacter pylori-associated ulcer disease among the Khakas people.

  5. Novel multimeric IL-1 receptor antagonist for the treatment of rheumatoid arthritis.

    Science.gov (United States)

    Pasi, Shweta; Kant, Ravi; Gupta, Sarika; Surolia, Avadhesha

    2015-02-01

    Protein therapeutics targeting inflammatory mediators have shown great promise for the treatment of autoimmunities such as rheumatoid arthritis (RA). However, a significant challenge in this area has been their low in vivo stability and consequently their severely compromised therapeutic efficacy. One such therapeutic molecule IL-1 receptor antagonist (IL-1ra), used in the treatment of rheumatoid arthritis, has displayed only modest efficacy in human clinical trials owing to its short biological half-life. Herein, we report a novel approach to conglomerate individual protein entities into a drug depot by incorporation of an amyloidogenic motif Lys-Phe-Phe-Glu (KFFE) thereby dramatically improving their systemic persistence and in turn their therapeutic efficacy in a mice model of autoimmune arthritis.

  6. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    Science.gov (United States)

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-05

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer.

  7. Lack of Association between an Interleukin-I Receptor Antagonist Gene Polymorphism and Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Victor A. Danis

    1994-01-01

    Full Text Available Non-MHC linked genes may contribute to genetic predisposition to the development of systemic lupus erythematosus. The possibility that cytokine genes may be involved was raised by the observation of increased frequency in expression of an uncommon allele of an interleukin-I receptor antagonist gene polymorphism and SLE in a recent U.K. study. We have not been able to show any significant differences in expression of this allele in SLE patients as a whole or in any patient subgroups. Our results actually show a slight decrease in the expression of this allele in SLE patients compared with healthy controls and in SLE patients with malar rash compared with SLE patients without malar rash.

  8. [Use of maraviroc, the first CCR5 receptor antagonist, in HIV treatment regimens].

    Science.gov (United States)

    Kravchenko, A V

    2013-01-01

    The paper gives the results of international trials of and guidelines for the use of maraviroc, the first CCR5 receptor antagonist, in treatment regimens for HIV-infected patients. The trials have convincingly shown that the maraviroc-containing antiretroviral therapy (ART) regimens are highly effective and safe for R5-tropic HIV-infected patients regardless of previous ART, baseline HIV RNA levels, and CD4+ lymphocyte count. Maraviroc can be recommended for HIV-infected patients who have previously received ART and who have been found to have a R5-tropic virus. The changes in the ART regimen and inclusion of maraviroc may be associated with both an ineffective previous treatment regimen and therapy-induced adverse events. In 2012, Russia's first reagent kit for the determination of HIV tropism was put to tests and registered at the Russian Inspectorate for the Protection of Consumer Rights and Human Welfare.

  9. New H2-receptor antagonist--roxatidine acetate--in treatment of duodenal ulcer.

    Science.gov (United States)

    Amarapurkar, D N; Parikh, S S; Desai, H G

    1993-08-01

    A double blind randomised trial, comparing a new H2-receptor antagonist, Roxatidine acetate, with Cimetidine was carried out in 47 patients of uncomplicated, endoscopically proven duodenal ulcer. Twenty seven patients were treated with Roxatidine 75 mg twice daily and 20 patients were treated with Cimetidine 200 mg 3 times a day and 400 mg at bed time for 4 weeks. At the end of 4 weeks, total pain relief was obtained in 74% and 70% patients receiving Roxatidine and Cimetidine respectively. Complete endoscopic healing at the end of 4 weeks was observed in 92.3% patients receiving Roxatidine and 85% patients receiving Cimetidine. These differences were statistically not significant. No significant side effects were observed in either group. We conclude that Roxatidine acetate is comparable to cimetidine in relieving pain and endoscopic healing of duodenal ulcer and has an excellent safety profile.

  10. GABAB Receptor Antagonist CGP46381 Inhibits Form-Deprivation Myopia Development in Guinea Pigs

    Directory of Open Access Journals (Sweden)

    Zhen-Ying Cheng

    2015-01-01

    Full Text Available The aim was to investigate the effects of the GABAB receptor antagonist, CGP46381, on form-deprivation myopia (FDM in guinea pigs. Twenty-four guinea pigs had monocular visual deprivation induced using a diffuser for 11 days (day 14 to 25. The deprived eyes were treated with daily subconjunctival injections (100 μl of either 2% CGP46381, 0.2% CGP46381, or saline or received no injection. The fellow eyes were left untreated. Another six animals received no treatment. At the start and end of the treatment period, ocular refractions were measured using retinoscopy and vitreous chamber depth (VCD and axial length (AL using A-scan ultrasound. All of the deprived eyes developed relative myopia (treated versus untreated eyes, P0.05. Subconjunctival injections of CGP46381 inhibit FDM development in guinea pigs in a dose-dependent manner.

  11. Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Kait Arefiev

    2011-01-01

    Full Text Available Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis.

  12. Asymmetric synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraine.

    Science.gov (United States)

    Xu, Feng; Zacuto, Michael; Yoshikawa, Naoki; Desmond, Richard; Hoerrner, Scott; Itoh, Tetsuji; Journet, Michel; Humphrey, Guy R; Cowden, Cameron; Strotman, Neil; Devine, Paul

    2010-11-19

    A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.

  13. Differential involvement of the opioid receptor antagonist naloxone in motivational and hedonic aspects of reward.

    Science.gov (United States)

    Schneider, Miriam; Heise, Verena; Spanagel, Rainer

    2010-04-02

    In the present study dose-dependent effects of the opioid receptor antagonist naloxone were investigated on the rewarding effects of sweetened condensed milk (SCM) in four behavioral paradigms addressing hedonic, consummatory as well as motivational aspects of a reward: odour-conditioned pleasure attenuation of the acoustic startle response (PAS), conditioned place preference (CPP), voluntary consumption in a limited access paradigm, as well as break point determination in a progressive ratio (PR) task. A dose-dependent reduction in reward-related behavior was observed in all paradigms, with exception of the break point in the PR task, which was not affected by naloxone at all. CPP for SCM was only affected by the highest dose of naloxone. The present results indicate that naloxone is more effective in suppressing the hedonic than motivational aspects of reward, further supporting the involvement of the endogenous opioid system in the mediation of hedonic properties of food reward.

  14. Ibuprofen protects ischemia-induced neuronal injury via up-regulating interleukin-1 receptor antagonist expression.

    Science.gov (United States)

    Park, E-M; Cho, B-P; Volpe, B T; Cruz, M O; Joh, T H; Cho, S

    2005-01-01

    The inflammatory response accompanies and exacerbates the developing injury after cerebral ischemia. Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to attenuate injuries in animal models of various neurological diseases. In the present study, we investigated ibuprofen's neuroprotective effects in rats exposed to transient forebrain ischemia and in cultures exposed to oxygen glucose deprivation (OGD). Rats treated with ibuprofen after transient forebrain ischemia displayed long-lasting protection of CA1 hippocampal neurons. There were selective increases in interleukin-1 receptor antagonist gene and protein expression in ibuprofen-treated OGD microglia. Furthermore, treatment with ibuprofen in neuron/microglia co-cultures increased the number of surviving HC2S2 neurons against OGD whereas IL-1ra neutralizing antibody reversed the ibuprofen-induced neuroprotection. The data indicate that ibuprofen-induced IL-1ra secretion is involved in neuroprotection against ischemic conditions.

  15. The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat

    DEFF Research Database (Denmark)

    Abelson, Klas S P; Höglund, A Urban

    2004-01-01

    Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as alpha2-adrenergic receptors. To fully understand these interactions, the effects...... of various receptor ligands on the cholinergic system must be investigated in detail. This study was initiated to investigate the effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine and the alpha2-adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors...... in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine...

  16. Design and synthesis of labeled analogs of PhTX-56, a potent and selective AMPA receptor antagonist

    DEFF Research Database (Denmark)

    Andersen, Trine F; Vogensen, Stine B; Jensen, Lars S

    2005-01-01

    antagonist of Ca2+-permeable AMPA receptors. PhTX-56 and its labeled derivatives are promising tools for structure-function studies of the ion channel of the AMPA receptor. We now describe the design and synthesis of 3H-, 13C-, and 15N-labeled derivatives of PhTX-56 for molecular level studies of AMPA....... These analogs can provide detailed information on the ligand-receptor interaction. In conclusion, synthesis of labeled derivatives of PhTX-56 provides important tools for future studies of the pore-forming region of AMPA receptors....

  17. Cannabinoid receptor-2 selective antagonist negatively regulates receptor activator of nuclear factor kappa B ligand mediated osteoclastogenesis

    Institute of Scientific and Technical Information of China (English)

    GENG De-chun; XU Yao-zeng; YANG Hui-lin; ZHU Guang-ming; WANG Xian-bin; ZHU Xue-song

    2011-01-01

    Background The cannabinoid receptor-2 (CB2) is important for bone remodeling. In this study, we investigated the effects of CB2 selective antagonist (AM630) on receptor activator of nuclear factor kappa B (RANK) ligand (RANKL)induced osteoclast differentiation and the underlying signaling pathway using a monocyte-macrophage cell line-RAW264.7.Methods RAW264.7 was cultured with RANKL for 6 days and then treated with AM630 for 24 hours. Mature osteoclasts were measured by tartrate-resistant acid phosphatase (TRAP) staining using a commercial kit. Total ribonucleic acid (RNA)was isolated and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) was done to examine the expression of RANK, cathepsin K (CPK) and nuclear factor kappa B (NF-κB). The extracellular signal-regulated kinase (ERK),phosphorylation of ERK (P-ERK) and NF-κB production were tested by Western blotting. The effect of AM630 on RAW264.7 viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay.Results AM630 did not affect the viability of RAW264.7. However, this CB2 selective antagonist markedly inhibited osteoclast formation and the inhibition rate was dose-dependent. The dose of >100 nmol/L could reduce TRAP positive cells to the levels that were significantly lower than the control. AM630 suppressed the expression of genes associated with osteoclast differentiation and activation, such as RANK and CPK. An analysis of a signaling pathway showed that AM630 inhibited the RANKL-induced activation of ERK, but not NF-κB.Conclusion AM630 could inhibit the osteoclastogenesis from RAW264.7 induced with RANKL.

  18. Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

    Science.gov (United States)

    Kym, Philip R; Souers, Andrew J; Campbell, Thomas J; Lynch, John K; Judd, Andrew S; Iyengar, Rajesh; Vasudevan, Anil; Ga