Further characterization of β3-adrenoceptors in the guinea pig gastric fundus: stereoselectivity, β-adrenoceptor alkylation, and structure-activity relationship

Abstract

The stereoselectivity of β3-adrenoceptors, the effect of a β-adrenoceptor alkylating agent, and the structure–activity relationship at β3-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 β1- and β2-adrenoceptors in the guinea pig atria and trachea, respectively. The concentration–response curves to the catecholamines ((–)-isoprenaline, (–)-noradrenaline, and (–)-adrenaline), the selective β3-adrenoceptor agonist BRL37344 ((R*,R*)-(±)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium), and the nonconventional partial β3-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 µM), the β-adrenoceptor alkylating agent. Furthermore, (±)-nadolol, which belongs to the aryloxy propanolamine class and has β1- and β2-adrenoceptor antagonistic characteristics, displays agonistic activity at β3-adrenoceptors. These results indicate that pharmacological characteristics of the β3-adrenoceptors of guinea pig gastric fundus differ from those of β1- and β2-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 β-hydroxyl group and the large moiety on the alkylamine chain characterized efficacy at β3-adrenoceptors.Key words: β3-adrenoceptor, stereoselectivity, β-adrenoceptor alkylating, structure–activity relationship, guinea pig gastric fundus.