TY - JOUR T1 - Effect of trimetoquinol analogs for antagonism of endoperoxide/thromboxane A2-mediated responses in human platelets and rat aorta. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1 LP - 9 VL - 232 IS - 1 AU - A Mukhopadhyay AU - S S Navran AU - H M Amin AU - S A Abdel-Aziz AU - J Chang AU - D J Sober AU - D D Miller AU - D R Feller Y1 - 1985/01/01 UR - http://jpet.aspetjournals.org/content/232/1/1.abstract N2 - 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. ER -