摘要：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 β-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 β1-adrenoceptor selectivity. The 3, 4-dimethoxy derivative showed the most potent positive inotropic effect and the highest selectivity to β1-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 β1-adrenoceptor selectivity of the derivatives with 3, 5-dihydroxy, 3- and 4-monohydroxy groups were essentially maintained. Among β1-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 β1-adrenoceptor agonists by the structural modification of a selective β2-adrenoceptor agonist, trimetoquinol. In this group of compounds, β-hydroxy moiety was suggested to be requisite to potent β-adrenoceptor stimulating action and 3, 4-dimethoxyphenethyl structure was important for manifestation of β1-adrenoceptor selectivity.
关键词：denopamine;denopamine derivarive;positive inotropic effect;structure-activity relationship;anesthetized dog
