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SR 58611A: a novel thermogenic beta-adrenoceptor agonist.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 1994 Jul 01; Vol. 259 (2), pp. 181-6. - Publication Year :
- 1994
-
Abstract
- 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.
- Subjects :
- Adenylyl Cyclases metabolism
Adipose Tissue, Brown enzymology
Adipose Tissue, Brown metabolism
Adrenergic beta-Antagonists pharmacology
Animals
Cyclic AMP analysis
Cyclic AMP biosynthesis
Drug Interactions
Glycerol metabolism
Imidazoles pharmacology
Lipid Metabolism
Male
Obesity drug therapy
Propanolamines pharmacology
Radioimmunoassay
Rats
Rats, Sprague-Dawley
Tetrahydronaphthalenes antagonists & inhibitors
Adipose Tissue, Brown drug effects
Adrenergic beta-Agonists pharmacology
Tetrahydronaphthalenes pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2999
- Volume :
- 259
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 7957612
- Full Text :
- https://doi.org/10.1016/0014-2999(94)90508-8