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. Epub 2017 Nov 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacology*
  • Appetite Regulation / drug effects*
  • Humans
  • Male
  • Mice
  • Obesity / drug therapy*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin / metabolism
  • Serotonin 5-HT2 Receptor Agonists / chemistry*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Taste Perception / drug effects


  • Anti-Obesity Agents
  • Pyridines
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • Serotonin