Functional identification of rat atypical β‐adrenoceptors by the first β3‐selective antagonists, aryloxypropanolaminotetralins

1 We have assessed the relative abilities of compounds belonging to the new aryloxypropanolaminotetralin (APAT) class and of the reference beta-adrenoceptor-blocking agent, alprenolol, to antagonize functional responses in vitro and in vivo involving atypical (beta(3)) Or conventional (beta(1) and beta(2)) beta-adrenoceptors. 2 The range of pA(2) values for three representative APATs against inhibition of spontaneous motility in the rat isolated colon by the selective beta(3)-adrenoceptor agonist, SR 58611A (8.1-8.8): was well above similarly calculated values for non-competitive antagonism of guinea-pig trachea relaxation by salbutamol (beta(2), 6.5-6.9) and the atrial chronotropic response by isoprenaline (beta(1), 6.7-7.3). Alprenolol, however, was substantially more potent in antagonizing atrial (pA(2), 8.2) and tracheal (pA(2), 8.9) responses than SR 58611A mediated inhibition of colonic motility (pA(2), 6.8). 3 Several APAT isomers with different configurations at the chiral carbons, when tested on isolated organs, presented stringent stereochemical requirements for beta(3)-selectivity, including high antagonist potency-ratios between active and inactive enantiomers. 4 In vivo, the inhibition of colonic motility and the thermogenic response of brown adipose tissue elicited in rats by the selective beta(3)-adrenoceptor agonists SR 58611A and BRL 37344 respectively were substantially diminished by the representative APAT, SR 59230A, at oral doses (less than or equal to 5 mg kg(-1)) well below those half maximally effective (ID50) for preventing beta(1)-(isoprenaline tachycardia greater than or equal to 80 mg kg(-1)) or beta(2)-(salbutamol bronchodilatation, 44 mg kg(-1)) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative beta(3)-responses. 5 These findings support APATs as the first potent, orally effective selective antagonists at beta(3)-adrenoceptors, and provide final unambiguous evidence that beta(3)-adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats.