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, 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.
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D015237:Dinoprost; D015232:Dinoprostone; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007536:Isomerism; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors*; D011458:Prostaglandins E / Q000037:antagonists & inhibitors; D011460:Prostaglandins F / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000037:antagonists & inhibitors*; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000494:pharmacology*
D007546:Isoquinolines; D011450:Prostaglandin Endoperoxides, Synthetic; D011458:Prostaglandins E; D011460:Prostaglandins F; D013189:SRS-A; D013931:Thromboxanes; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D014213:Tretoquinol; D015232:Dinoprostone