Pharmacological evaluation of the β-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues

Abstract

The β 1− and β 2-adrenoceptor agonist and U46619 (a thromboxane A 2 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 inatria and trachea, and the rank order of β-adrenoceptor agonist potency was I>II>III>IV>V>VI. Whereas N-substitution reduced potency for β-agonism, the β 2/β 1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) β 2-selectivity than I. Propanolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the β-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(−)-TMQ>R(+)-TMQ, and a β 2/β 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>VI>II=III>IV>V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and β 2/β 1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain β 2-selectivity and give a different activity profile for β-adrenoceptor activation vs. endoperoxide/thromboxane A 2 antagonism.