title: Selective beta 1-adrenoceptor agonist activity of denopamine and its derivatives in dogs.
abstract: 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.
authors.affiliation: Pharmacological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yabana
authors.forename: S
authors.initials: S
authors.lastname: Murata
authors.forename: H
authors.initials: H
authors.lastname: Narita
authors.forename: R
authors.initials: R
authors.lastname: Shimizu
authors.forename: T
authors.initials: T
authors.lastname: Miyagishima
authors.forename: M
authors.initials: M
authors.lastname: Takeda
authors.forename: T
authors.initials: T
authors.lastname: Nagao
mesh_terms: D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D002395:Catecholamines / Q000494:pharmacology; D004285:Dogs; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007441:Intubation, Gastrointestinal; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014213:Tretoquinol / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D004983:Ethanolamines; C059333:T 1583; C025342:RP333; D014213:Tretoquinol; D007545:Isoproterenol; C037293:denopamine