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Functional identification of rat atypical β‐adrenoceptors by the first β 3 ‐selective antagonists, aryloxypropanolaminotetralins
Author(s) -
Manara Luciano,
Badone Domenico,
Baroni Marco,
Boccardi Giovanni,
Cecchi Roberto,
Croci Tiziano,
Giudice Antonina,
Guzzi Umberto,
Landi Marco,
Fur Gérard
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15209.x
Subject(s) - alprenolol , chronotropic , chemistry , agonist , antagonist , isoprenaline , in vivo , pharmacology , partial agonist , bronchodilatation , endocrinology , medicine , salbutamol , receptor , biology , heart rate , biochemistry , stimulation , asthma , blood pressure , microbiology and biotechnology
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 (β 3 ) or conventional (β 1 and β 2 ) β‐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 β 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 (β 2 , 6.5–6.9) and the atrial chronotropic response by isoprenaline (β 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 β 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 β 3 ‐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 (ID 50 ) for preventing β 1 ‐(isoprenaline tachycardia ≥80 mg kg −1 ) or β 2 ‐(salbutamol bronchodilatation, 44 mg kg −1 ) mediated responses. Alprenolol, as expected, was a less potent and nonselective antagonist of the putative β 3 ‐responses. 5 These findings support APATs as the first potent, orally effective selective antagonists at β 3 ‐adrenoceptors, and provide final unambiguous evidence that β 3 ‐adrenoceptors underlie inhibition of colonic motility and brown adipose tissue thermogenesis in rats