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

• Published in: British journal of pharmacology Vol. 117; no. 3; pp. 435 - 442
• Main Authors: Manara, Luciano, Badone, Domenico, Baroni, Marco, Boccardi, Giovanni, Cecchi, Roberto, Croci, Tiziano, Giudice, Antonina, Guzzi, Umberto, Landi, Marco, Fur, Gérard
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-1996; Nature Publishing
• Subjects: Aryloxypropanolaminotetralins; atypical β‐adrenoceptors; Biological and medical sciences; Cell receptors; Cell structures and functions; Fundamental and applied biological sciences. Psychology; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); rat BAT thermogenesis; rat isolated colon; selective β3‐adrenoceptor antagonists; β3‐adrenoceptors; Motility; Rat; Rodentia; Gut; Brown adipose tissue; In vitro; Biological activity; β-Adrenergic receptor; In vivo; Vertebrata; Mammalia; Thermogenesis; Animal; Antagonist; Colon
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15209.x

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