Abstract
N(2S)-7-carbethoxymethoxy-1,2,3,4-tetrahydropanaphth-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 EC 50 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 EC 50 of 11 ± 0.4 nM. Only at doses higher than 10 μM did the non-selective β-adrenoceptor antagonist, propranolol and alprenolol, as well as the selective β 1-andβ 2-adrenoceptor antagonist, (±)-[2-(3-carbomoyl-4-hydroxyphenoxy ethylaminol]-3[4(1-methyl-4-trifluoromethyl-2-imidazolyl)-phenoxy]-2 propanol (CGP 20712A) and erythro-(+-)-1-(7- methylindan-4-yloxy)-3-iso-propylaminobutan-2-ol-hydrochloride (ICI 118,551), antagonize the SR 58611A-induced stimulation of both adenylyl cyclase activity and lipid metabolism. Since, at high dose, all these β-adrenoceptor antagonist lack selectivity for β 1-orβ 2-adrenoceptors, these results suggest that the β-adrenoceptor agonist, SR 58611A, activates thermogenesis by act on brown fat cell β 3-adrenoceptors. This implies that this compound might be useful for treatment of obesity.
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