Selective beta 1-adrenoceptor agonist activity of denopamine and its derivatives in dogs

Cardiovascular effects of intravenously administered denopamine and its derivatives were investigated in anesthetized dogs and their positive inotropic and hypotensive effects were compared. Structure-activity relationships were examined by modifying the methoxy group in ring B and the hydroxy group in ring A in structure II, a ring-fissioned product of trimetoquinol. Almost all test compounds demonstrated positive inotropic and chronotropic effects as well as hypotensive effects which were mediated by beta-adrenoceptors. With modification of the methoxy group in ring B, only 3,4-dimethoxy, 2,3,4-trimethoxy and 3,4,5-trimethoxy derivatives exhibited beta 1-adrenoceptor selectivity. The 3,4-dimethoxy derivative showed the most potent positive inotropic effect and the highest selectivity to beta 1-adrenoceptor. By structural modification of the hydroxyl group in ring A of the 3,4-dimethoxy derivatives, the potency of positive inotropic effect was affected, while beta 1-adrenoceptor selectivity of the derivatives with 3,5-dihydroxy, 3- and 4-monohydroxy groups were essentially maintained. Among beta 1-adrenoceptor selective compounds, the dose ratios between intravenous and intraduodenal administrations of catechol derivatives like isoproterenol were higher than those of non-catechol derivatives. The 4-monohydroxy derivative (racemic denopamine) exhibited the smallest dose ratio with a long-lasting action. Thus, we could identify selective beta 1-adrenoceptor agonists by the structural modification of a selective beta 2-adrenoceptor agonist, trimetoquinol. In this group of compounds, beta-hydroxy moiety was suggested to be requisite to potent beta-adrenoceptor stimulating action and 3,4-dimethoxyphenethyl structure was important for manifestation of beta 1-adrenoceptor selectivity.