A PHARMACOLOGICAL CHARACTERIZATION OF THE 5-HYDROXYTRYPTAMINE(2) (5-HT(2)) RECEPTOR IN THE ISOLATED RABBIT AORTA WITH TRYPTAMINE ANALOGS, AND COMPETITIVE AND NONSURMOUNTABLE ANTAGONISTS: ANALYSES WITH STEADY-STATE AND KINETIC METHODS.
Item
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Title
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A PHARMACOLOGICAL CHARACTERIZATION OF THE 5-HYDROXYTRYPTAMINE(2) (5-HT(2)) RECEPTOR IN THE ISOLATED RABBIT AORTA WITH TRYPTAMINE ANALOGS, AND COMPETITIVE AND NONSURMOUNTABLE ANTAGONISTS: ANALYSES WITH STEADY-STATE AND KINETIC METHODS.
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Identifier
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AAI8801694
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identifier
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8801694
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Creator
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CLANCY, BRIAN MATTHEW.
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Contributor
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Saul Maayani
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Date
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1987
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Pharmacology
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Abstract
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The 5-HT{dollar}\sb2{dollar} receptor in the isolated rabbit aorta was characterized with eighteen tryptamine analogs and four competitive and two nonsurmountable antagonists of the response to 5-HT. Drug-receptor interactions were investigated with steady-state methods and a novel kinetics method. All tryptamine analogs were agonists and their dissociation constants and relative intrinsic efficacies were determined. Structure-activity observations revealed two trends. First, mono- and dimethylation of the side-chain nitrogen selectively decreased drug efficacy. Second, minor modifications of the indole ring resulted in parallel increases or decreases in drug affinity and efficacy. These results provide some information about structural requirements necessary for the development of competitive antagonists from simple tryptamine derivatives which would be useful for the classification of 5-HT{dollar}\sb2{dollar} receptors in other systems. The kinetics of agonist and antagonist interactions were studied by following antagonist-induced decreases in the steady-state response to an agonist. A model was fitted to the data and it yielded estimates of the association and dissociation rate constants of the agonist and the antagonist. Calculated dissociation constants (k{dollar}\sb{lcub}\rm -x{rcub}{dollar}/k{dollar}\sb{lcub}\rm x{rcub}{dollar}) agreed with those determined with steady-state methods. The kinetic rate constants of the high affinity antagonists were similar to those previously reported in high affinity binding studies. The results suggest that the association rate constant is the primary determinant of drug affinity and that the kinetic rate constants reflect molecular interactions of these drugs with the receptor. Lysergic acid diethylamide (LSD) and 2-iodo-LSD (IOL) were nonsurmountable antagonists of the response to 5-HT. Results of steady-state and kinetic experiments indicated that LSD and IOL bound to the 5-HT-recognition site on 5-HT{dollar}\sb2{dollar} receptors. It is proposed that these antagonist-receptor complexes interact with the transducer system in an undefined manner, possibly resulting in the formation of a slowly reversible ternary complex.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
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Program
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Biomedical Sciences
