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

Journal of Medicinal Chemistry
Javier García-CárcelesMaría L López-Rodríguez

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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Citations

Jan 11, 2019·PloS One·Miguel Toro-SazoBruce K Cassels
Sep 12, 2018·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jia Zhou, Kathryn A Cunningham
Jan 1, 2021·Expert Opinion on Pharmacotherapy·Michael L Mathai
Aug 15, 2018·Journal of Medicinal Chemistry·Eric A WoldJia Zhou

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