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

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Abstract
1 We have assessed the relative abilities of compounds belonging to the new aryloxypropanolaminotetralin (APAT) class and of the reference β-adrenoceptor-blocking agent, alprenolol, to antagonize functional responses in vitro and in vivo involving atypical (β3) or conventional (β1 and β2) β-adrenoceptors. 2 The range of pA2 values for three representative APATs against inhibition of spontaneous motility in the rat isolated colon by the selective β3-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 (β2, 6.5–6.9) and the atrial chronotropic response by isoprenaline (β1, 6.7-7.3). Alprenolol, however, was substantially more potent in antagonizing atrial (pA2, 8.2) and tracheal (pA2, 8.9) responses than SR 58611A mediated inhibition of colonic motility (pA2, 6.8). 3 Several APAT isomers with different configurations at the chiral carbons, when tested on isolated organs, presented stringent stereochemical requirements for β3-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 β3-adrenoceptor agonists SR 58611A and BRL 37344 respectively were substantially diminished by the representative APAT, SR 59230A, at oral doses (≤5 mg kg−1) well below those half maximally effective (ID50) for preventing β1-(isoprenaline tachycardia ≥80 mg kg−1) or β2-(salbutamol bronchodilatation, 44 mg kg−1) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative β3-responses. 5 These findings support APATs as the first potent, orally effective selective antagonists at β3-adrenoceptors, and provide final unambiguous evidence that β3-adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats