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Sample records for alprenolol

  1. Binding of fluorescent and radiolabelled alprenolol to intact cultured brain cells and liposomes

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    Maderspach, K.; Nemecz, Gy.; Mesude Yigiter (Magyar Tudomanyos Akademia Biologiai Kutato Koezpontja, Szeged)

    1981-01-01

    Beta-adrenergic antagonist L-alprenolol was labelled for radioactivity and UV fluorescence, and the binding to intact cultured chicken brain cells under equilibrium conditions, as the model of the experiments in vivo, was probed. The application of fluorescent label did not explore any cell type or cell particle with enhanced binding. The analysis of the radiolabelled alprenolol-binding revealed a non-specific accumulation on the surface of these cells, which was inhibited by unlabelled alprenolol excess, however, this is the peculiarity of the specific binding. The authors' results emphasize that for the characterization of membrane receptors of intact cells, the accurate separation of specific and non-specific binding is required. The application of a ligand concentration as low as possible and a very effective washing procedure for the removal of the unbound (and the bulk of the nonspecifically bound) label are recommended.

  2. Conjugation of ß-Adrenergic Antagonist Alprenolol to Implantable Polymer-Aescin Matrices for Local Delivery

    OpenAIRE

    Ewa Oledzka; Dagmara Pachowska; Marcin Sobczak; Agnieszka Lis-Cieplak; Grzegorz Nalecz-Jawecki; Anna Zgadzaj; Waclaw Kolodziejski

    2015-01-01

    The sustained release of alprenolol, a ß-adrenergic antagonist, could be beneficial for the treatment of various heart diseases while reducing the side effects resulting from its continuous use. The novel and branched copolymers uniquely composed of biodegradable components (lactide and glycolide) have been synthesized using natural and therapeutically-efficient ß-aescin-initiator, and consequently characterized to determine their structures and physicochemical properties. The obtained matric...

  3. Conjugation of ß-Adrenergic Antagonist Alprenolol to Implantable Polymer-Aescin Matrices for Local Delivery

    Directory of Open Access Journals (Sweden)

    Ewa Oledzka

    2015-09-01

    Full Text Available The sustained release of alprenolol, a ß-adrenergic antagonist, could be beneficial for the treatment of various heart diseases while reducing the side effects resulting from its continuous use. The novel and branched copolymers uniquely composed of biodegradable components (lactide and glycolide have been synthesized using natural and therapeutically-efficient ß-aescin-initiator, and consequently characterized to determine their structures and physicochemical properties. The obtained matrices were not cyto- and genotoxic towards bacterial luminescence, protozoan, and Salmonella typhimurium TA1535. The copolymers release the drug in vitro in a sustained manner and without burst release. The value of the drug released was strongly dependent on the copolymer composition and highly correlated with the hydrolytic matrices’ degradation results.

  4. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: Comparisons with β1-selective esmolol and nonselective propranolol and alprenolol

    Directory of Open Access Journals (Sweden)

    Hironori eTsuchiya

    2013-12-01

    Full Text Available Although β1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective β1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and nonselective β1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β1-selective landiolol and esmolol and nonselective propranolol and alprenolol at 0.5–200 µM. The membrane interactivity and the antioxidant activity were determined by measuring fluorescence polarization and by peroxidizing membrane lipids with peroxynitrite, respectively. Nonselective β1-blockers, but not selective ones, intensively acted on 1,2-dipalmitoylphosphatidylcholine liposomal membranes and cardiomyocyte-mimetic membranes to increase the membrane fluidity. Landiolol and its inactive metabolite distinctively decreased the fluidity of 1,2-dipalmitoylphosphatidylcholine liposomal membranes, suggesting that a membrane-rigidifying effect is attributed to the morpholine moiety in landiolol structure but unlikely to clinically contribute to the β1-blocking effect of landiolol. Propranolol and alprenolol interacted with lipid raft model membranes, whereas neither landiolol nor esmolol. All drugs fluidized mitochondria-mimetic membranes and inhibited the membrane lipid peroxidation with the potency correlating to their membrane interactivity. Landiolol is characterized as a drug devoid of the interactivity with membrane lipid rafts relating to β2-adrenergic receptor blockade. The differentiation between β1-blocking selectivity and nonselectivity is compatible with that between membrane noninteractivity and interactivity. The mitochondrial membrane fluidization by landiolol independent of blocking β1-adrenergic receptors is responsible for the antioxidant cardioprotection common to

  5. Characteristic interactivity of landiolol, an ultra-short-acting highly selective β1-blocker, with biomimetic membranes: Comparisons with β1-selective esmolol and non-selective propranolol and alprenolol

    OpenAIRE

    Hironori eTsuchiya; Maki eMizogami

    2013-01-01

    Although β1-blockers have been perioperatively used to reduce the cardiac disorders associated with general anesthesia, little is known about the mechanistic characteristics of ultra-short-acting highly selective β1-blocker landiolol. We studied its membrane-interacting property in comparison with other selective and nonselective β1-blockers. Biomimetic membranes prepared with phospholipids and cholesterol of varying compositions were treated with β1-selective landiolol and esmolol and nonsel...

  6. Proton NMR study of the interactions of catecholamines with phospholipids from chicken erythrocyte membranes

    Energy Technology Data Exchange (ETDEWEB)

    Varoucha, D.

    1985-01-01

    High-resolution NMR spectroscopy has been applied to the study of the interaction of catecholamines, norepinephrine, epinephrine, isoproterenol and their antagonists propranolol and alprenolol with sonicated phospholipids extracted from chicken erythrocyte membranes (CEM). The catecholamine molecules are immobilized by the phospholipids of CEM and the magnitude of the effect seems to depend on the alkyl substitution of their amino group. Upon introduction of alprenolol and propranolol into phospholipid vesicles a broadening of the resonances of the n-methyl alkyl chain and the terminal methyl protons was observed. The results present evidence about the specificity of the interactions of catecholamines with phospholipids from CEM.

  7. Alterations of the membrane-bound adenyl-cyclase enzyme and beta-receptors in developing glia- and neuron tissue cultures

    International Nuclear Information System (INIS)

    The development of beta-receptors was investigated on the basis of specific 3H-L-dihydro-alprenolol (DHA) binding. The dependence of the binding on time and concentration the dissociation constant and the number of receptor sites on one cell were determined. It is concluded that the number of 3H-DHA binding sites significantly increases after preincubation with beta-agonists and in mixed glia-neuron cultures. (L.E.)

  8. The influence of radiation sterilisation on some {beta}-blockers in the solid state

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    Marciniec, B. [Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 6 Gruwaldzka Str., 60-780 Poznan (Poland); Ogrodowczyk, M., E-mail: mogrodo@ump.edu.pl [Department of Pharmaceutical Chemistry, Poznan University of Medical Sciences, 6 Gruwaldzka Str., 60-780 Poznan (Poland); Czajka, B.; Hofman, M. [Department of Cooridinational Chemistry, A. Mickiewicz University, Grunwaldzka 6, 60-780 Poznan (Poland)

    2011-02-20

    Research highlights: {yields} Six {beta}-blockers (acebutolol, alprenolol, atenolol, metoprolol, pindolol, propranolol) in solid phase were exposed to the ionising radiation by e-beam in doses from 25 to 400 kGy. {yields} To establish the effects of irradiation on their physico-chemical properties, the compounds were then analysed by DSC, SEM, XRD and FT-IR. {yields} For alprenolol, propranolol and metoprolol linear relations were found between the irradiation dose and the decrease in the melting point (r = 0.9446-0.9864). {yields} No changes were observed in the FT-IR spectra and in the SEM images of the compounds studied. - Abstract: Six derivatives of aryloxyalkylaminopropanol of known {beta}-adrenolytic activity (acebutolol, alprenolol, atenolol, metoprolol, pindolol, propranolol) in solid phase were exposed to the ionising radiation generated by e-beam of high-energy electrons from an accelerator ({approx}10 MeV) in doses from 25 to 400 kGy. To establish the effects of irradiation on their physico-chemical properties, the compounds were then analysed by differential scanning calorimetry (DSC), scanning electron microscope (SEM), X-ray diffraction (XRD) and FT-IR spectrometry. The standard sterilisation dose (25 kGy) was found to cause no changes in only one derivative - acebutolol, whereas in the other derivatives the irradiation caused colour changes, differences in X-ray diffraction patterns and in the character of DSC curves, including a decrease in the melting point. For each derivative one clear peak corresponding to the process of melting was observed and its position shifted towards lower temperatures with increasing dose of irradiation. For all compounds studied the value of the shift was between 0.1 and 1.0 {sup o}C. For alprenolol, propranolol and metoprolol linear relations were found between the irradiation dose and the decrease in the melting point, described by the correlation coefficient (between 0.9446 and 0.9864). No changes were observed in

  9. Drug: D01182 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01182 Drug Alprenolol hydrochloride (JP16/USAN); Regletin (TN) C15H23NO2. HCl 285....1496 285.8096 D01182.gif Anti-adrenergic [beta-receptor] Therapeutic category: 2123 ATC code: C07AA01 beta1-adr...energic receptor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adr...+155) Calcium signaling pathway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adr...] map07037 Antiarrhythmic drugs map07214 beta-Adrenergic receptor agonists/antago

  10. The influence of radiation sterilisation on some β-blockers in the solid state

    International Nuclear Information System (INIS)

    Research highlights: → Six β-blockers (acebutolol, alprenolol, atenolol, metoprolol, pindolol, propranolol) in solid phase were exposed to the ionising radiation by e-beam in doses from 25 to 400 kGy. → To establish the effects of irradiation on their physico-chemical properties, the compounds were then analysed by DSC, SEM, XRD and FT-IR. → For alprenolol, propranolol and metoprolol linear relations were found between the irradiation dose and the decrease in the melting point (r = 0.9446-0.9864). → No changes were observed in the FT-IR spectra and in the SEM images of the compounds studied. - Abstract: Six derivatives of aryloxyalkylaminopropanol of known β-adrenolytic activity (acebutolol, alprenolol, atenolol, metoprolol, pindolol, propranolol) in solid phase were exposed to the ionising radiation generated by e-beam of high-energy electrons from an accelerator (∼10 MeV) in doses from 25 to 400 kGy. To establish the effects of irradiation on their physico-chemical properties, the compounds were then analysed by differential scanning calorimetry (DSC), scanning electron microscope (SEM), X-ray diffraction (XRD) and FT-IR spectrometry. The standard sterilisation dose (25 kGy) was found to cause no changes in only one derivative - acebutolol, whereas in the other derivatives the irradiation caused colour changes, differences in X-ray diffraction patterns and in the character of DSC curves, including a decrease in the melting point. For each derivative one clear peak corresponding to the process of melting was observed and its position shifted towards lower temperatures with increasing dose of irradiation. For all compounds studied the value of the shift was between 0.1 and 1.0 oC. For alprenolol, propranolol and metoprolol linear relations were found between the irradiation dose and the decrease in the melting point, described by the correlation coefficient (between 0.9446 and 0.9864). No changes were observed in the FT-IR spectra and in the SEM images

  11. Effect of selective blockade of oxygen consumption, glucose transport, and Ca2+ influx on thyroxine action in human mononuclear cells

    DEFF Research Database (Denmark)

    Kvetny, J; Matzen, L E

    1990-01-01

    The effect of selective blockade of cellular glucose transporters, Ca2+ influx, and mitochondrial oxygen consumption on thyroxine (T4)-stimulated oxygen consumption and glucose uptake was examined in human mononuclear blood cells. Blockade of glucose transporters by cytochalasin B (1 x 10(-5) mol...... had no effect on glucose uptake. We conclude that T4-stimulated glucose uptake in human mononuclear blood cells is dependent on intact glucose transporters and Ca2+ influx, but not on mitochondrial oxygen consumption. However, oxygen consumption is, in part, dependent on intact glucose uptake......./L) and of Ca2+ influx by alprenolol (1 x 10(-5) mol/L) and verapamil (4 x 10(-4) mol/L) inhibited T4-activated glucose uptaken and reduced T4-stimulated oxygen consumption by 20%. Uncoupling of mitochondrial oxygen consumption by azide (1 x 10(-3) mol/L) inhibited T4-stimulated oxygen consumption, but...

  12. Up-regulation of β-adrenoreceptors by drugs which cause depression

    International Nuclear Information System (INIS)

    A number of drugs associated with depressive episodes in man were investigated for their effects on rat cortical β-adrenoceptors, in view of the down-regulation of β-adrenoceptors caused by chronic administration of anti-depressant drugs. Scatchard analyses of [3H]dihydro-alprenolol binding data provided Bmax and KD values for the cortical β-adrenoceptors. Up-regulation of the receptors occurred after daily injections of phenobarbitone for seven days (by 55%), pentobarbitone (by 143%), reserpine (by 82%) and propranolol (by 64%). β-adrenoceptors were not affected by daily injections of clonidine, chlorpromazine and flupenthixol for seven days. This work confirms the up-regulatory effect on β-adrenoceptors of certain drugs which produce depressions in man

  13. Flow Cytometric Quantification of Peripheral Blood Cell β-Adrenergic Receptor Density and Urinary Endothelial Cell-Derived Microparticles in Pulmonary Arterial Hypertension.

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    Jonathan A Rose

    Full Text Available Pulmonary arterial hypertension (PAH is a heterogeneous disease characterized by severe angiogenic remodeling of the pulmonary artery wall and right ventricular hypertrophy. Thus, there is an increasing need for novel biomarkers to dissect disease heterogeneity, and predict treatment response. Although β-adrenergic receptor (βAR dysfunction is well documented in left heart disease while endothelial cell-derived microparticles (Ec-MPs are established biomarkers of angiogenic remodeling, methods for easy large clinical cohort analysis of these biomarkers are currently absent. Here we describe flow cytometric methods for quantification of βAR density on circulating white blood cells (WBC and Ec-MPs in urine samples that can be used as potential biomarkers of right heart failure in PAH. Biotinylated β-blocker alprenolol was synthesized and validated as a βAR specific probe that was combined with immunophenotyping to quantify βAR density in circulating WBC subsets. Ec-MPs obtained from urine samples were stained for annexin-V and CD144, and analyzed by a micro flow cytometer. Flow cytometric detection of alprenolol showed that βAR density was decreased in most WBC subsets in PAH samples compared to healthy controls. Ec-MPs in urine was increased in PAH compared to controls. Furthermore, there was a direct correlation between Ec-MPs and Tricuspid annular plane systolic excursion (TAPSE in PAH patients. Therefore, flow cytometric quantification of peripheral blood cell βAR density and urinary Ec-MPs may be useful as potential biomarkers of right ventricular function in PAH.

  14. Flow Cytometric Quantification of Peripheral Blood Cell β-Adrenergic Receptor Density and Urinary Endothelial Cell-Derived Microparticles in Pulmonary Arterial Hypertension

    Science.gov (United States)

    Rose, Jonathan A.; Wanner, Nicholas; Cheong, Hoi I.; Queisser, Kimberly; Barrett, Patrick; Park, Margaret; Hite, Corrine; Naga Prasad, Sathyamangla V.; Erzurum, Serpil; Asosingh, Kewal

    2016-01-01

    Pulmonary arterial hypertension (PAH) is a heterogeneous disease characterized by severe angiogenic remodeling of the pulmonary artery wall and right ventricular hypertrophy. Thus, there is an increasing need for novel biomarkers to dissect disease heterogeneity, and predict treatment response. Although β-adrenergic receptor (βAR) dysfunction is well documented in left heart disease while endothelial cell-derived microparticles (Ec-MPs) are established biomarkers of angiogenic remodeling, methods for easy large clinical cohort analysis of these biomarkers are currently absent. Here we describe flow cytometric methods for quantification of βAR density on circulating white blood cells (WBC) and Ec-MPs in urine samples that can be used as potential biomarkers of right heart failure in PAH. Biotinylated β-blocker alprenolol was synthesized and validated as a βAR specific probe that was combined with immunophenotyping to quantify βAR density in circulating WBC subsets. Ec-MPs obtained from urine samples were stained for annexin-V and CD144, and analyzed by a micro flow cytometer. Flow cytometric detection of alprenolol showed that βAR density was decreased in most WBC subsets in PAH samples compared to healthy controls. Ec-MPs in urine was increased in PAH compared to controls. Furthermore, there was a direct correlation between Ec-MPs and Tricuspid annular plane systolic excursion (TAPSE) in PAH patients. Therefore, flow cytometric quantification of peripheral blood cell βAR density and urinary Ec-MPs may be useful as potential biomarkers of right ventricular function in PAH. PMID:27270458

  15. Bromoacetylated analogue of cyanopindolol: an irreversible antagonist at rat beta-adrenoceptors

    International Nuclear Information System (INIS)

    A high affinity, chemically reactive cyanopindolol derivative N8-bromoacetyl-N1-3'-(2-cyano-4-indolyloxy)-2'-hydroxypropyl-[Z]-1,8-diamino-p-menthane (Br-CYP) was synthesized and its interaction with β-adrenoceptors characterized. Studies with rat heart, lung, brain and red blood cell membranes indicated that the compound displaced 3H-dihydroalprenolol (3H-DHA) from β-adrenoceptors with IC50 values in the nanomolar range. The concentration of functional β-adrenoceptors in membranes was markedly reduced when membranes were preincubated with Br-CYP and then extensively washed prior to assay. (+/-)Alprenolol and (-)isoproterenol, but not (+)isoproterenol, when included in the preincubation prevented this reduction in binding sites by Br-CYP. Br-CYP was active in vivo when injected intraperitoneally into rats. A dose of 10 μg/kg reduced the concentration of binding sites in membranes from heart by 30%, lung by 36%, and RBC by 70%, but did not affect sites on brain membranes 16 hours after injection. Higher doses blocked virtually all the 3H-DHA binding sites in the peripheral organs studied. These results suggest that Br-CYP may be a useful compound for in vivo studies of the biochemistry and pharmacology of β-adrenergic systems. 27 references, 4 figures, 3 tables

  16. Alpha-2 adrenergic and serotonin-1B receptors in the OK cell, an opossum kidney cell line

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    Murphy, T.J.

    1988-01-01

    Alpha-2 adrenergic and serotonin-1B (5HT{sub 1B}) receptors, both negatively-coupled to adenylyl cyclase, were characterized in the OK cell line, a renal proximal tubule epithelial cell line derived from the kidney of a North American opossum. In membrane saturation radioligand binding experiments, ({sup 3}H)yohimbine and ({sup 3}H)rauwolscine labeled an equivalent number of binding sites. Detailed pharmacological analysis of OK cell alpha-2 adrenergic receptors in competition binding assays indicate this receptor is neither an alpha-2A nor an alpha-2B adrenergic receptor subtype, although the alpha-2B receptor subtype-selective drugs prazosin, ARC-239 and chlorpromazine have affinities for OK cell alpha-2 adrenergic receptors similar to those at the alpha-2B receptor subtype. Determinations of agonist potency for inhibition of PTH-stimulated cyclic AMP production and radioligand binding analysis using ({sup 125}I)({minus})-cyanopindolol indicate that a 5HT{sub 1B} receptor is expressed in the OK cell line. A biochemical effector system coupled to this receptor subtype has not been previously described. Several compounds appear to be potent agonists at the 5TH{sub 1B} receptor including the beta adrenergic antagonists cyanopindolol, pindolol, propranolol and alprenolol.

  17. Alpha-2 adrenergic and serotonin-1B receptors in the OK cell, an opossum kidney cell line

    International Nuclear Information System (INIS)

    Alpha-2 adrenergic and serotonin-1B (5HT1B) receptors, both negatively-coupled to adenylyl cyclase, were characterized in the OK cell line, a renal proximal tubule epithelial cell line derived from the kidney of a North American opossum. In membrane saturation radioligand binding experiments, [3H]yohimbine and [3H]rauwolscine labeled an equivalent number of binding sites. Detailed pharmacological analysis of OK cell alpha-2 adrenergic receptors in competition binding assays indicate this receptor is neither an alpha-2A nor an alpha-2B adrenergic receptor subtype, although the alpha-2B receptor subtype-selective drugs prazosin, ARC-239 and chlorpromazine have affinities for OK cell alpha-2 adrenergic receptors similar to those at the alpha-2B receptor subtype. Determinations of agonist potency for inhibition of PTH-stimulated cyclic AMP production and radioligand binding analysis using [125I](-)-cyanopindolol indicate that a 5HT1B receptor is expressed in the OK cell line. A biochemical effector system coupled to this receptor subtype has not been previously described. Several compounds appear to be potent agonists at the 5TH1B receptor including the beta adrenergic antagonists cyanopindolol, pindolol, propranolol and alprenolol

  18. Interaction of the cationic form of amphiphilic drugs with phosphatidylcholine model membranes. Competition with lanthanide ions.

    Science.gov (United States)

    Westman, J; Eriksson, L E; Ehrenberg, A

    1984-01-01

    Model membranes (liposomes) of egg yolk phosphatidylcholine were exposed to the charged (cationic) form of amphiphilic drugs (procaine, tetracaine, metroprolol, alprenolol and propranolol). Drug analysis by ultraviolet light absorption of the bulk solution after centrifugation separation was used to determine the amount of drug bound to the membranes. Microelectrophoresis was employed to measure the change in the zeta-potential after drug adsorption. Binding constants were derived by simulating the experimental curves with a theoretical model which considers the electrostatic effects (Gouy-Chapman theory). Analogous experiments were carried out for the adsorption of Eu3+. Metal analysis was made by three different methods. Good agreement between the centrifugation and electrophoresis experiments was obtained for reasonable positions of the plane of shear relative to the positional plane of the bound ions. Displacement of Eu3+ from vesicles upon addition of drug cations was followed by 31P-NMR. The competition experiments were numerically simulated. The Eu3+ binding was assumed to obey a mass action type equilibrium, whereas the drug binding was described by a Henry's law partition. The binding constants for the drugs in the competition experiments followed the same order as in the absence of Eu3+. However, the numerical values had to be reduced. The effect of anions was studied. PMID:17005132

  19. Characterization of phosphorylated beta-adrenergic receptors from desensitized turkey erythrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Rebar, R.; Crooke, S.T.; Stadel, J.M.

    1986-05-01

    Catecholamine-induced desensitization of turkey erythrocyte (TE) adenylate cyclase results in a 40-50 percent decrease in agonist stimulated cyclase activity. Desensitization is accompanied by decreased mobility on SDS-PAGE of beta-adrenergic receptor (BAR) proteins photoaffinity labeled with (/sup 125/I)-p-azidobenzylcarazolol compared to control. Using a low crosslinked gel, the M/sub r/ = 42,000 band of BAR from desensitized TE was further resolved into a doublet compared to a single M/sub r/ = 38,000 band for control. The formation of the doublet appears to correlate with the amount of adenylate cyclase desensitization. Preincubating TE for 20 hr at 37/sup 0/C with /sup 32/P-/sub i/ labels BAR. /sup 32/P-BAR was partially purified by affinity chromatography over alprenolol-Sepharose. Limited digest peptide maps of /sup 32/P-BAR using papain identified a unique peptide (M/sub r/ = 2800) from BAR of desensitized TE which was absent in control. This unique /sup 32/P-peptide was found only in the upper band of the doublet of BAR from desensitized TE. These data indicate that BAR is not uniformly phosphorylated following agonist-induced desensitization of TE and identify a peptide of BAR which is a site of phosphorylation correlating with desensitization of TE adenylate cyclase.

  20. Sensitive enantioanalysis of β-blockers via field-amplified sample injection combined with water removal in microemulsion electrokinetic chromatography.

    Science.gov (United States)

    Ma, Yanhua; Zhang, Huige; Rahman, Zia Ur; Wang, Weifeng; Li, Xi; Chen, Hongli; Chen, Xingguo

    2014-10-01

    In this study, an on-line sample preconcentration technique, field-amplified sample injection combined with water removal by electroosmotic flow (EOF) pump, was applied to realize a highly sensitive chiral analysis of β-blocker enantiomers by MEEKC. The introduction of a water plug in capillary before the electrokinetic injection provided the effective preconcentration of chiral compounds. And then the water was moving out of the column from the injection end under the effect of the EOF, which avoided dilution of the stacked β-blocker enantiomers concentration suffering from the presence of water in separation buffer. Moreover, the addition of H3 PO4 and methanol in the sample solution greatly improved the enhancement efficiency further. Under optimized conditions, more than 2700-fold enhancement in sensitivity was obtained for each enantiomer of bupranolol (BU), alprenolol (AL), and propranolol (PRO) via electrokinetic injection. LODs were 0.10, 0.10, 0.12, 0.11, 0.02, and 0.02 ng/mL for S-BU, R-BU, S-AL, R-AL, S-PRO, and R-PRO, respectively. Eventually, the proposed method was successfully applied to the determination of BU, AL, and PRO in serum samples with good recoveries ranging from 93.4 to 98.2%. PMID:24798241

  1. Reduced number of alpha- and beta-adrenergic receptors in the myocardium of rats exposed to tobacco smoke

    Energy Technology Data Exchange (ETDEWEB)

    Larue, D.; Kato, G.

    1981-04-09

    The concentration of alpha- and beta-adrenergic receptors--as measured by specific (/sup 3/H)WB-4101 and (-)-(/sup 3/H)dihydroalprenolol binding--was diminished by 60% below control values in the hearts of rats exposed to tobacco smoke. These changes in receptor numbers took place almost immediately after tobacco smoke exposure and were rapidly reversible after termination of the exposure. The dissociation constant, KD, for (/sup 3/H)WB-4101 was identical in exposed (KD . 0.34 +/- 0.09 nM) and control (KD . 0.35 +/- 0.07 nM) hearts but was significantly different in the case of (-)-(3H)dihydroalprenolol binding (exposed, KD . 2.83 +/- 0.30 mM vs. control KD . 5.22 +/- 0.61 nM). For beta-receptor binding there was no significant difference between exposed and control animals in the Ki values for (-)-epinephrine, (-)-norepinephrine, (-)-alprenolol, (+/-)-propranolol or timolol. (-)-Isoproterenol, however, was found to bind with lower affinity in exposed compared with control hearts. For alpha-receptor binding there was no significant difference between control and 'smoked' animals in the Ki values for (-)-epinephrine, (-0)-norepinephrine or phentolamine. The decrease in alpha- and beta-adrenergic receptor concentration may be related to the phenomenon of receptor desensitization resulting from a release of catecholamines in rats exposed to tobacco smoke.

  2. Novel benzodioxopiperazines acting as antagonists at postsynaptic 5-HT1A receptors and as agonists at 5-HT1A autoreceptors: a comparative pharmacological characterization with proposed 5-HT1A antagonists.

    Science.gov (United States)

    Millan, M J; Canton, H; Gobert, A; Lejeune, F; Rivet, J M; Bervoets, K; Brocco, M; Widdowson, P; Mennini, T; Audinot, V

    1994-01-01

    The novel benzodioxopiperazines [4-(benzodioxan-5-yl)1-[2- (benzocyclobutane-1-yl)ethyl]piperazine] (S 14489), [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine)] (S 15535) and [4-(benzodioxan-5-yl)1-[2(indan-1-yl)ethyl]piperazine (S15931) competitively displaced the binding of [3H]-8-OH-DPAT at serotonin (5-HT)1A receptors with affinities (pKis) of 9.2, 8.8 and 8.9, respectively. These values compared favorably with those of the structurally related eltoprazine (8.0) and the proposed 5-HT1A antagonists NAN-190 (9.2), MDL 73005 EF (8.9), SDZ 216-525 (8.8), BMY 7378 (8.7), (-)-tertatolol (8.1), (-)-alprenolol (7.7), WAY 100,135 (7.5) and spiperone (6.9). The affinities of S 14489, S 15535 and S 15931 for other 5-HT receptor types (5-HT1B, 5-HT1C, 5-HT1D, 5-HT2 and 5-HT3) were about 50 to 1000-fold lower. The spontaneous tail-flicks, flat-body posture and hypothermia mediated by an action of the 5-HT1A agonist 8-OH-DPAT at postsynaptic 5-HT1A receptors were dose-dependently and completely antagonized by S 14489, S 15535 and S15931 at doses of 0.63 to 10.0 and 2.5 to 40.0 mg/kg for s.c. and oral administration, respectively. They did not induce these responses alone, and in their presence, dose-response curves for 8-OH-DPAT were shifted in parallel to the right without loss of maximal effect. By contrast, eltoprazine, MDL 73005 EF, BMY 7378 and NAN-190 behaved as "partial" agonists and only incompletely antagonized the actions of 8-OH-DPAT in these tests. At 5-HT1A autoreceptors, S 14489, S 15535 and S 15931 acted as agonists in inhibiting striatal 5-hydroxytryptophan accumulation (0.16-2.5 mg/kg, s.c.) and in abolishing the electrical activity of the dorsal raphe nucleus (0.005-0.100 mg/kg, i.v.). Eltoprazine, BMY 7378, NAN-190 and MDL 73005 EF also behaved as agonists at these 5-HT1A autoreceptors, whereas WAY 100,135, spiperone, (-)-tertatolol, (-)-alprenolol and SDZ 216-525 inhibited neither accumulation nor firing. WAY 100,135 and spiperone antagonized the inhibition

  3. The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

    Science.gov (United States)

    Prichard, B N

    1978-01-01

    All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III). PMID:26370

  4. High affinity dopamine D2 receptor radioligands. 2. [125I]epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors

    International Nuclear Information System (INIS)

    Epidepride, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 nM MgCl2. Scatchard analysis of in vitro binding to striatal, medical frontal cortical, hippocampal and cerebellar membranes revealed a KD of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC50's for inhibition of [125I]epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 μM to >10 μM. Partial displacement of [125I]epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to α2 noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent KD of 9 nM. At an epidepride concentration equal to the KD for the D2 receptor, i.e., 25 pM, no striatal α2 binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the α2 site. Correlation of inhibition of [3H]spiperone and [125I]epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site

  5. Antagonism by 8-hydroxy-2(di-n-propylamino)tetraline and other serotonin agonists of muscarinic M1-type receptors coupled to inositol phospholipid breakdown in human IMR-32 and SK-N-MC neuroblastoma cells

    International Nuclear Information System (INIS)

    IMR-32 and SK-N-MC cells were found to contain [3H]quinuclidinyl benzilate specific binding sites inhibited by pirenzepine in a manner suggesting the presence of both M1-type and M2-type muscarinic receptor recognition sites. Neither cell had detectable [3H]8-OH-DPAT binding sites. Carbachol stimulated the rate of inositol phospholipid breakdown in IMR-32 and SK-N-MC human neuroblastoma cells with an EC50 value of about 50 μM in both cases. Pirenzepine inhibited the carbachol stimulated inositol phospholipid breakdown in both cells with Hill slopes of unity and IC50 values of 15 nM (IMR-32) and 12 nM (SK-N-MC). The 5-HT1A receptor agonist 8-OH-DPAT competitively inhibited carbachol-stimulated inositol phospholipid breakdown with pA2 values of 5.78 (IMR-32) and 5.61 (SK-N-MC). The 5-HT agonists 5-MeODMT and buspirone at micromolar concentrations inhibited carbachol-stimulated breakdown in IMR-32 cells. The inhibition by 8-OH-DPAT and 5-MeODMT was not affected by preincubation with (-)alprenolol. 5-HT was without effect on either basal or carbachol-stimulated breakdown. It is concluded that IMR-32 and SK-N-MC neuroblastoma cells express muscarinic M1-type but not serotoninergic receptors coupled to phosphoinositide-specific phospholipase C. 8-OH-DPAT acts as a weak antagonist at these muscarinic receptors

  6. Search for β2 adrenergic receptor ligands by virtual screening via grid computing and investigation of binding modes by docking and molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Qifeng Bai

    Full Text Available We designed a program called MolGridCal that can be used to screen small molecule database in grid computing on basis of JPPF grid environment. Based on MolGridCal program, we proposed an integrated strategy for virtual screening and binding mode investigation by combining molecular docking, molecular dynamics (MD simulations and free energy calculations. To test the effectiveness of MolGridCal, we screened potential ligands for β2 adrenergic receptor (β2AR from a database containing 50,000 small molecules. MolGridCal can not only send tasks to the grid server automatically, but also can distribute tasks using the screensaver function. As for the results of virtual screening, the known agonist BI-167107 of β2AR is ranked among the top 2% of the screened candidates, indicating MolGridCal program can give reasonable results. To further study the binding mode and refine the results of MolGridCal, more accurate docking and scoring methods are used to estimate the binding affinity for the top three molecules (agonist BI-167107, neutral antagonist alprenolol and inverse agonist ICI 118,551. The results indicate agonist BI-167107 has the best binding affinity. MD simulation and free energy calculation are employed to investigate the dynamic interaction mechanism between the ligands and β2AR. The results show that the agonist BI-167107 also has the lowest binding free energy. This study can provide a new way to perform virtual screening effectively through integrating molecular docking based on grid computing, MD simulations and free energy calculations. The source codes of MolGridCal are freely available at http://molgridcal.codeplex.com.

  7. Identification of the binding subunit of the D/sub 1/-dopamine receptor by photoaffinity crosslinking

    Energy Technology Data Exchange (ETDEWEB)

    Amlaiky, N.; Berger, J.G.; Chang, W.; McQuade, R.D.; Caron, M.G.

    1986-03-01

    A derivative of the potent D/sub 1/ antagonist SCH-23390 has been synthesized. This compound, (R,S)-1-(m-aminophenyl)-7-chloro-8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-38548), has been radioiodinated by a chloramine T procedure yielding 3 radioiodinated products. One of these separated isomers (R/sub f/ = 0.35; CH/sub 2/Cl/sub 2/:MEOH:TEA; 82.5:17.5:0.1 on TLC) binds reversibly to rat striatal membranes with high affinity (K/sub D/ approx. 80 pM) appropriate stereoselectivity and D/sub 1/-dopaminergic specificity. (/sup 125/I)SCH-38548 can be covalently incorporated into a peptide of M/sub r/ approx. 72,000 using the heterobifunctional crosslinking reagent N-succinimidyl-6-(4'-azido-2'-nitro-phenylamino) hexanoate. Covalent incorporation of (/sup 125/I) SCH-38548 into the M/sub r/ approx. 72,000 peptide can be blocked by dopaminergic agents with D/sub 1/-dopaminergic specificity (for agonists: SKF 38393 > apomorphine > dopamine; for antagonists: SCH-23390 > cis-flupentixol >>> trans-flupentixol). The D/sub 1/-dopaminergic selectivity and specificity of the labeling was further demonstrated by the fact that other antagonists such as domperidone, ketanserin, phentolamine and alprenolol did not compete for the covalent labeling of the M/sub r/ approx. 72,000 peptide. This new radioligand should be useful in the molecular characterization of the D/sub 1/-dopaminergic receptor from various sources.

  8. High affinity dopamine D2 receptor radioligands. 2. ( sup 125 I)epidepride, a potent and specific radioligand for the characterization of striatal and extrastriatal dopamine D2 receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Ansari, M.S.; Schmidt, D.E.; de Paulis, T.; Clanton, J.A.; Manning, R.G.; Gillespie, D. (Vanderbilt Univ., Nashville, TN (United States)); Innis, R.; Al-Tikriti, M. (Yale Univ., New Haven, CT (United States))

    1991-01-01

    Epidepride, (S)-N-((1-ethyl-2-pyrrolidinyl)methyl)-5-iodo-2,3-dimethoxybenzamide, the iodine analogue of isoremoxipride (FLB 457), was found to be a very potent dopamine D2 receptor antagonist. Optimal in vitro binding required incubation at 25C for 4 h at pH 7.4 in a buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl{sub 2} and 1 nM MgCl{sub 2}. Scatchard analysis of in vitro binding to striatal, medical frontal cortical, hippocampal and cerebellar membranes revealed a K{sub D} of 24 pM in all regions, with Bmax's of 36.7, 1.04, 0.85, and 0.37 pmol/g tissue, respectively. The Hill coefficients ranged from 0.91-1.00 in all four regions. The IC{sub 50}'s for inhibition of ({sup 125}I)epidepride binding to striatal, medial frontal cortical, and hippocampal membranes for SCH 23390, SKF 83566, serotonin, ketanserin, mianserin, naloxone, QNB, prasozin, clonidine, alprenolol, and norepinephrine ranged from 1 {mu}M to >10 {mu}M. Partial displacement of ({sup 125}I)epidepride by nanomolar concentrations of clonidine was noted in the frontal cortex and hippocampus, but not in the striatum. Scatchard analysis of epidepride binding to {alpha}{sub 2} noradrenergic receptors in the frontal cortex and hippocampus revealed an apparent K{sub D} of 9 nM. At an epidepride concentration equal to the K{sub D} for the D2 receptor, i.e., 25 pM, no striatal {alpha}{sub 2} binding was seen and only 7% of the specific epidepride binding in the cortex or hippocampus was due to binding at the {alpha}{sub 2} site. Correlation of inhibition of ({sup 3}H)spiperone and ({sup 125}I)epidepride binding to striatal membranes by a variety of D2 ligands revealed a correlation coefficient of 0.99, indicating that epidepride labels a D2 site.

  9. Sorption of structurally different ionized pharmaceutical and illicit drugs to a mixed-mode coated microsampler.

    Science.gov (United States)

    Peltenburg, Hester; Timmer, Niels; Bosman, Ingrid J; Hermens, Joop L M; Droge, Steven T J

    2016-05-20

    The mixed-mode (C18/strong cation exchange-SCX) solid-phase microextraction (SPME) fiber has recently been shown to have increased sensitivity for ionic compounds compared to more conventional sampler coatings such as polyacrylate and polydimethylsiloxane (PDMS). However, data for structurally diverse compounds to this (prototype) sampler coating are too limited to define its structural limitations. We determined C18/SCX fiber partitioning coefficients of nineteen cationic structures without hydrogen bonding capacity besides the charged group, stretching over a wide hydrophobicity range (including amphetamine, amitriptyline, promazine, chlorpromazine, triflupromazine, difenzoquat), and eight basic pharmaceutical and illicit drugs (pKa>8.86) with additional hydrogen bonding moieties (MDMA, atenolol, alprenolol, metoprolol, morphine, nicotine, tramadol, verapamil). In addition, sorption data for three neutral benzodiazepines (diazepam, temazepam, and oxazepam) and the anionic NSAID diclofenac were collected to determine the efficiency to sample non-basic drugs. All tested compounds showed nonlinear isotherms above 1mmol/L coating, and linear isotherms below 1mmol/L. The affinity for C18/SCX-SPME for tested organic cations without Hbond capacities increased with longer alkyl chains, ranging from logarithmic fiber-water distribution coefficients (log Dfw) of 1.8 (benzylamine) to 5.8 (triflupromazine). Amines smaller than benzylamine may thus have limited detection levels, while cationic surfactants with alkyl chain lengths >12 carbon atoms may sorb too strong to the C18/SCX sampler which hampers calibration of the fiber-water relationship in the linear range. The log Dfw for these simple cation structures closely correlates with the octanol-water partition coefficient of the neutral form (Kow,N), and decreases with increased branching and presence of multiple aromatic rings. Oxygen moieties in organic cations decreased the affinity for C18/SCX-SPME. Log Dfw values of