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

Alban Lepailleur; Damien Geslin; Johanna Giovannini; Bertrand Cuissart; Jean-Luc Lamotte; Ronan Bureau

doi:10.1016/j.drudis.2026.104600

Mapping ligands for MT₁/MT₂ and 5-HT_2C receptors: Chemotypes, SAR, and polypharmacology

Drug Discov Today. 2026 Jan 8;31(2):104600. doi: 10.1016/j.drudis.2026.104600. Online ahead of print.

Authors

Alban Lepailleur¹, Damien Geslin², Johanna Giovannini², Bertrand Cuissart³, Jean-Luc Lamotte³, Ronan Bureau²

Affiliations

¹ Université Caen Normandie, Normandie Univ, CERMN UR4258, F-14000 Caen, France. Electronic address: alban.lepailleur@unicaen.fr.
² Université Caen Normandie, Normandie Univ, CERMN UR4258, F-14000 Caen, France.
³ Université Caen Normandie, Normandie Univ, GREYC UMR - CNRS, ENSICAEN, F-14000 Caen, France.

PMID: 41519433
DOI: 10.1016/j.drudis.2026.104600

Abstract

Understanding ligand selectivity and efficacy at melatonin (MT₁, MT₂) and serotonin (5-HT_2C) receptors remains a key challenge in central nervous system (CNS) drug discovery. Ligands combining MT₁/MT₂ 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.

Keywords: 5-HT(2C) serotonin receptor; melatonin receptors; polypharmacology; structure–activity relationships (SARs).

Publication types

Review