Research article summary (published 3 Feb 2008):

Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization.

Full 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.

Author information

Author/s: Thomsen, William J (WJ); Grottick, Andrew J (AJ); Menzaghi, Frederique (F); Reyes-Saldana, Hazel (H); Espitia, Stephen (S); Yuskin, Diane (D); Whelan, Kevin (K); Martin, Michael (M); Morgan, Michael (M); Chen, Weichao (W); Al-Shamma, Hussien (H); Smith, Brian (B); Chalmers, Derek (D); Behan, Dominic (D);

Affiliation: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121, USA. bthomsen(-atsign-)arenapharm.com

Journal and publication information

Publication Type: Journal Article

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2008-May; vol 325 (issue 2) : pp 577-87

Dates: Created 2008/04/18; Completed 2008/05/19;

PMID: 18252809, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Aminopyridines - pharmacology Animals Behavior, Animal - drug effects Benzazepines - blood; pharmacokinetics; pharmacology Body Weight - drug effects Brain - drug effects; metabolism Cell Line Dopamine - metabolism Eating - drug effects Fluorobenzenes - pharmacology Humans Indoles - pharmacology

Male Norepinephrine - metabolism Obesity - drug therapy; physiopathology Piperidines - pharmacology Rats Rats, Sprague-Dawley Receptor, Serotonin, 5-HT2C - agonists; antagonists & inhibitors; physiology Recombinant Proteins - agonists; antagonists & inhibitors; genetics Serotonin - metabolism Serotonin Agonists - blood; pharmacokinetics; pharmacology Serotonin Antagonists - pharmacology Transfection

Associated Chemicals: 8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (0) ; Aminopyridines (0) ; Benzazepines (0) ; Fluorobenzenes (0) ; Indoles (0) ; Piperidines (0) ; Receptor, Serotonin, 5-HT2C (0) ; Recombinant Proteins (0) ; SB 242084 (0) ; Serotonin Agonists (0) ; Serotonin Antagonists (0) ; MDL 100907 (139290-65-6) ; Serotonin (50-67-9) ; Norepinephrine (51-41-2) ; Dopamine (51-61-6)

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