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

Drug Discovery Today 2026 Open access

Read full text
Authors: Alban Lepailleur, Damien Geslin, Johanna Giovannini, Bertrand Cuissart, Jean-Luc Lamotte, Ronan Bureau
DOI: 10.1016/j.drudis.2026.104600
Cited by: 1
References: 99

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.

Fields of Study & Subjects

Circadian rhythm and melatonin Neurotransmitter Receptor Influence on Behavior Nicotinic Acetylcholine Receptors Study

Publication details

Journal / source
Drug Discovery Today
Publisher
Elsevier BV
Volume
31
Issue
2
Pages
104600–104600
Publication date
9 January 2026
Language
EN