SR 58611A: a novel thermogenic beta-adrenoceptor agonist.
N(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl]-(2R )-2-hydroxy-2-(3-chlorophenyl)ethanamine hydrochloride (SR 58611A) increased cyclic AMP levels in membrane homogenates from rat interscapular brown adipose tissue with an EC50 of 20 +/- 2 nM. Substitution of GTP with the GDP analog, guanosine-5'-O[thiodiphosphate], in the incubation medium suppressed the stimulation of adenylyl cyclase activity by SR 58611A. This compound also stimulated glycerol release from the brown fat cells, with an EC50 of 11 +/- 0.4 nM. Only at doses higher than 10 microM did the non-selective beta-adrenoceptor antagonists, propranolol and alprenolol, as well as the selective beta 1- and beta 2-adrenoceptor antagonists, (+-)-[2-(3-carbamoyl-4-hydroxy-phenoxy)- ethylamino]-3-[4(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP 20712A) and erythro-(+-)-1-(7-methylindan-4-yloxy)-3-iso-propylamino butan-2-ol-hydrochloride (ICI 118,551), antagonize the SR 58611A-induced stimulation of both adenylyl cyclase activity and lipid metabolism. Since, at high doses, all these beta-adrenoceptor antagonists lack selectivity for beta 1- or beta 2-adrenoceptors, these results suggest that the beta-adrenoceptor agonist, SR 58611A, activates thermogenesis by acting on brown fat cell beta 3-adrenoceptors. This implies that this compound might be useful for treatment of obesity.
Department of Biomedical Sciences and Biotechnologies, School of Medicine, University of Brescia, Italy.
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D000262:Adenylyl Cyclases / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000032:analysis / Q000096:biosynthesis; D004347:Drug Interactions; D005990:Glycerol / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy; D011412:Propanolamines / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D011412:Propanolamines; D013764:Tetrahydronaphthalenes; C026777:ICI 118551; C049763:CGP 20712A; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D005990:Glycerol; C076252:amibegron