Work

Mapping ligands for MT1/MT2 and 5-HT2C receptors: Chemotypes, SAR, and polypharmacology

Year: 2026

Type: article

Abstract: Understanding ligand selectivity and efficacy at melatonin (MT 1 , MT 2 ) and serotonin (5-HT 2C ) receptors remains a key challenge in central nervous system (CNS) drug discovery. Ligands combining MT 1 /MT 2 agonism with 5-HT 2C antagonism are of therapeutic relevance in depression and circadian rhythm disorders. This review provides a comprehensive overview of ligands reported for these receptors in ChEMBL, with an emphasis on compounds evaluated across multiple targets. A pharmacophore-based approach was applied to group ligands by shared features, revealing pharmacomodulations influencing receptor selectivity and polypharmacology. Together, these insights can inspire the rational design of selective or polypharmacological ligands, offering new opportunities for multitarget drug discovery.

Source: Drug Discovery Today

DOI: 10.1016/j.drudis.2026.104600

Authors: Alban Lepailleur, Damien Geslin, Johanna Giovannini, Bertrand Cuissart, Jean-Luc Lamotte, Ronan Bureau