Selective β_1-Adrenoceptor Agonist Activity of Denopamine and Its Derivatives in Dogs

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概要

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• 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 β_1-adrenoceptor selectivity. The 3,4-dimethoxy derivative showed the most potent positive inotropic effect and the highest selectivity to β_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 β_1-adrenoceptor selectivity of the derivatives with 3,5-dihydroxy, 3- and 4-monohydroxy groups were essentially maintained. Among β_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 β_1-adrenoceptor agonists by the structural modification of a selective β_2-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 β_1-adrenoceptor selectivity.

• 公益社団法人日本薬学会の論文
• 1993-05-15

著者

• 宮城島 利一

  Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.

• 長尾 拓

  Department Of Toxicology And Pharmacology Faculty Of Pharmaceutical Sciences University Of Tokyo

• 村田 栄

  Pharmacological Research Laboratory Tanabe Seiyaku Co. Ltd.

• 矢花 秀雄

  Department Of Toxicology And Pharmacology Faculty Of Pharmaceutical Sciences University Of Tokyo

• 宮城島 利一

  Organic Chemistry Research Laboratory Tanabe Seiyaku Co. Ltd.

• 清水 良

  Research Laboratory Of Applied Biochemistry Tanabe Seiyaku Co. Ltd.

• 矢花 秀雄

  Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd.,

• 成田 寛

  Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd.,

• 武田 幹雄

  Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.,

• 成田 寛

  Pharmacological Research Laboratory Tanabe Seiyaku Co. Ltd.

• 武田 幹雄

  Organic Chemistry Research Laboratory Tanabe Seiyaku Co. Ltd.

• 宮城島 利一

  Organic Chemistry Research Laboratory, Tanabe Seiyaku Co., Ltd.,

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