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Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2008 May; Vol. 325 (2), pp. 577-87. Date of Electronic Publication: 2008 Feb 05. - Publication Year :
- 2008
-
Abstract
- 5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.
- Subjects :
- Aminopyridines pharmacology
Animals
Behavior, Animal drug effects
Benzazepines blood
Benzazepines pharmacokinetics
Body Weight drug effects
Brain drug effects
Brain metabolism
Cell Line
Dopamine metabolism
Fluorobenzenes pharmacology
Humans
Indoles pharmacology
Male
Norepinephrine metabolism
Obesity drug therapy
Obesity physiopathology
Piperidines pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2C physiology
Recombinant Proteins agonists
Recombinant Proteins antagonists & inhibitors
Recombinant Proteins genetics
Serotonin metabolism
Serotonin 5-HT2 Receptor Antagonists
Serotonin Antagonists pharmacology
Serotonin Receptor Agonists blood
Serotonin Receptor Agonists pharmacokinetics
Transfection
Benzazepines pharmacology
Eating drug effects
Serotonin 5-HT2 Receptor Agonists
Serotonin Receptor Agonists pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1521-0103
- Volume :
- 325
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 18252809
- Full Text :
- https://doi.org/10.1124/jpet.107.133348