2. Academic Validation
  3. A Positive Allosteric Modulator of the Serotonin 5-HT2C Receptor for Obesity

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

  • J Med Chem. 2017 Dec 14;60(23):9575-9584. doi: 10.1021/acs.jmedchem.7b00994.
Javier García-Cárceles 1,  Juan M Decara 2,  Henar Vázquez-Villa 1,  Ramón Rodríguez 3,  Eva Codesido 3,  Jacobo Cruces 3,  José Brea 4,  María I Loza 4,  Francisco Alén 2,  Joaquin Botta 5,  Peter J McCormick 6,  Juan A Ballesteros 7,  Bellinda Benhamú 1,  Fernando Rodríguez de Fonseca 2,  María L López-Rodríguez 1
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica I, Universidad Complutense de Madrid , E-28040 Madrid, Spain.
  • 2 Unidad de Gestión Clínica de Salud Mental, Instituto IBIMA, Hospital Regional Universitario , E-29010 Málaga, Spain.
  • 3 Galchimia , E-15823 O Pino, A Coruña, Spain.
  • 4 Biofarma Research Group, USEF Screening Platform, CIMUS, USC , E-15782 Santiago de Compostela, Spain.
  • 5 School of Pharmacy, University of East Anglia , NR4 7TJ Norwich, U.K.
  • 6 School of Veterinary Medicine, University of Surrey , GU2 7XH Guildford, U.K.
  • 7 Vivia Biotech S.L. , Parque Científico de Madrid, E-28760 Madrid, Spain.
PMID: 29116785 DOI: 10.1021/acs.jmedchem.7b00994
Abstract

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 antiobesity 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 behavior of compound 11 identified in this work supports the interest of a serotonin 5-HT2CR PAM as a promising therapeutic approach for obesity.

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