title: Further characterization of beta3-adrenoceptors in the guinea pig gastric fundus: stereoselectivity, beta-adrenoceptor alkylation, and structure-activity relationship.
abstract: The stereoselectivity of beta3-adrenoceptors, the effect of a beta-adrenoceptor alkylating agent, and the structure-activity relationship at beta3-adrenoceptors were investigated on the guinea pig gastric fundus. Isomeric activity ratios ((+)/(-)) for isomers of isoprenaline and noradrenaline were 20.9-fold and 43.7-fold, respectively, and were less than those obtained for activation of beta1- and beta2-adrenoceptors in the guinea pig atria and trachea, respectively. The concentration-response curves to the catecholamines ((-)-isoprenaline, (-)-noradrenaline, and (-)-adrenaline), the selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium), and the nonconventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A ((+/-)-[4-[3-[(1,1-dimethylethyl) amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride) were resistant to blockade by (+/-)-pindobind (10 microM), the beta-adrenoceptor alkylating agent. Furthermore, (+/-)-nadolol, which belongs to the aryloxypropanolamine class and has beta1- and beta2-adrenoceptor antagonistic characteristics, displays agonistic activity at beta3-adrenoceptors. These results indicate that pharmacological characteristics of the beta3-adrenoceptors of guinea pig gastric fundus differ from those of beta1- and beta2-adrenoceptors. (-)-Noradrenaline and (-)-adrenaline were more potent than dopamine and (-)-phenylephrine, respectively. In addition, dobutamine was 22-fold more potent than dopamine. These results suggest that the 4-hydroxyl group at the catechol ring and the beta-hydroxyl group and the large moiety on the alkylamine chain characterized efficacy at beta3-adrenoceptors.
authors.affiliation: Department of Chemical Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Horinouchi
authors.forename: K
authors.initials: K
authors.lastname: Koike
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D000081005:Cyclohexane Monoterpenes; D005748:Gastric Fundus / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D010869:Pindolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000318:Adrenergic beta-Agonists; D000081005:Cyclohexane Monoterpenes; D022702:Receptors, Adrenergic, beta-3; D012702:Serotonin Antagonists; C084712:pindobind; D010869:Pindolol