title: Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues.
abstract: The beta 1- and beta 2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta, respectively. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than II greater than III greater than IV greater than V greater than VI. Whereas N-substitution reduced potency for beta-agonism, the beta 2/beta 1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) beta 2-selectivity than I. Propranolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the beta-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ greater than R(+)-TMQ, and a beta 2/beta 1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I greater than VI greater than II = III greater than IV greater than V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and beta 2/beta 1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain beta 2-selectivity and give a different activity profile for beta-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000318:Adrenergic beta-Agonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011433:Propranolol; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013931:Thromboxanes / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D007546:Isoquinolines; D011450:Prostaglandin Endoperoxides, Synthetic; D013931:Thromboxanes; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011433:Propranolol; D014213:Tretoquinol; D007545:Isoproterenol; D007213:Indomethacin