Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta
The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced aggregatory and secretory responses in platelets,...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 232; no. 1; pp. 1 - 9 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.01.1985
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Subjects | |
Online Access | Get full text |
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Summary: | The pharmacological properties of a limited series of tetrahydro-isoquinoline [trimetoquinol (TMQ)] analogs for inhibition
of endoperoxide (U46619)-mediated responses in human platelets and rat aorta were examined. All analogs blocked U46619-induced
aggregatory and secretory responses in platelets, and contraction of rat aorta in a concentration-dependent manner. R-(+)-TMQ
was a competitive-type inhibitor of U46619-induced contractions of rat aorta. The relative inhibitory potency for TMQ analogs
against U46619-induced effects was TMQ greater than N-methyl TMQ greater than or equal to erythro-alpha-methyl TMQ greater
than threo-alpha-methyl TMQ greater than or equal to alpha-dimethyl TMQ. R-(+)-TMQ and the azoprostanoid analog (U51605) were
potent antagonists of U46619 action in rat aorta with pA2 values of 5.97 and 5.70, respectively. Other experiments indicated
that U51605 was a partial agonist and R-(+)-TMQ was an inhibitor of U51605-induced contractions of rat aorta (pKB = 5.94).
R-(+)-TMQ also blocked prostaglandin E2-mediated responses in rat aorta (pA2 = 5.46) but was ineffective as an antagonist
of prostaglandin F2 alpha and LTD4 responses in dog iris sphincter and guinea-pig trachea or lung parenchyma, respectively.
The data indicate that 1) the TMQ analogs were antagonists of endoperoxide/thromboxane A2-mediated responses in rat aorta
and human platelets involving a similar mechanism of action and 2) stereochemical requirements of these TMQ analogs for activation
of beta adrenoceptors and antagonism of endoperoxide/thromboxane A2-mediated responses are different. It is concluded that
selectivity for these two pharmacological properties of TMQ can be achieved by appropriate stereochemical modification of
the tetrahydroisoquinoline nucleus. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |