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A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity

García-Cárceles, J, Decara, JM, Vázquez-Villa, H, Rodríguez, R, Codesido, E, Cruces, J, Brea, J, Loza, MI, Alén, F, Botta, J , McCormick, Peter, Ballesteros, JA, Benhamú, B, Rodríguez de Fonseca, F and López-Rodríguez, ML (2017) A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity Journal of Medicinal Chemistry, 60 (23). pp. 9575-9584.

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The 5-HT2CR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HT2CR allosteric modulators as safer anti-obesity drugs, a chemical library from Vivia Biotech was screened using ExviTech® platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HT2AR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS-related malaise. The behaviour of compound 11 identified in this work supports the interest of a serotonin 5-HT2CR PAM as a promising therapeutic approach for obesity.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Veterinary Medicine
Authors :
García-Cárceles, J
Decara, JM
Vázquez-Villa, H
Rodríguez, R
Codesido, E
Cruces, J
Brea, J
Loza, MI
Alén, F
Botta, J
Ballesteros, JA
Benhamú, B
Rodríguez de Fonseca, F
López-Rodríguez, ML
Date : 24 December 2017
DOI : 10.1021/acs.jmedchem.7b00994
Copyright Disclaimer : Copyright 2017 American Chemical Society
Depositing User : Melanie Hughes
Date Deposited : 24 Oct 2017 08:05
Last Modified : 08 Nov 2018 02:08

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