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标题：Selective β1-Adrenoceptor Agonist Activity of Denopamine and Its Derivatives in Dogs
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作者：Hideo YABANA ; Sakae MURATA ; Hiroshi NARITA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1993
卷号：16
期号：5
页码：471-474
DOI：10.1248/bpb.16.471
出版社：The Pharmaceutical Society of Japan
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