Pharmacological evaluation of the beta-adrenoceptor agonist properties of N-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist properties of trimetoquinol (TMQ, I) and N-benzyl ring substituted TMQ analogues (II, 4'-methylbenzylTMQ; III, 4'-chloro-benzylTMQ; IV, 4'-methoxybenzylTMQ; V, 4'-nitrobenzylTMQ; VI, 3',4'-dichlorobenzylTMQ; and VII, 4'-aminobenzylTMQ) were studied in guinea pig atria and trachea. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than VII greater than II greater than V greater than IV greater than VI greater than III and I greater than VII greater than IV = VI greater than V greater than III greater than II, respectively. Whereas the N-benzyl substitution reduced potency for beta-agonist activity, the beta 2/beta 1-selectivity ratio was enhanced by addition of groups to the N-benzyl ring, and the rank order of beta 2-selectivity was VI (10-fold) greater than III (8-fold) = IV (8-fold) greater than VII (3-fold) greater than V = I greater than II. The results show that varying the nature of substituents on the N-benzyl ring of TMQ produces compounds which retain greater beta 2-selectivity.