Mapping ligands for MT1/MT2 and 5-HT2C receptors: Chemotypes, SAR, and polypharmacology
Understanding ligand selectivity and efficacy at melatonin (MT<sub>1</sub>, MT<sub>2</sub>) and serotonin (5-HT<sub>2C</sub>) receptors remains a key challenge in central nervous system (CNS) drug discovery. Ligands combining MT<sub>1</sub>/MT<sub>2</sub> agonism with 5-HT<sub>2C</sub> 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.
Authors
- Johanna Giovannini (ORCID: https://orcid.org/0000-0002-3088-5853)
- Damien Geslin (ORCID: https://orcid.org/0000-0002-5039-2837)
- Alban Lepailleur (ORCID: https://orcid.org/0000-0003-0202-1588)
- Jean-Luc Lamotte
- Bertrand Cuissart
- Ronan Bureau
Institutions
- Centre National de la Recherche Scientifique (FR)
- Normandie Université (FR)
- Université de Caen Normandie (FR)
Publication Details
- Journal
- Drug Discovery Today
- Published
- 2026-01-09
- DOI
- https://doi.org/10.1016/j.drudis.2026.104600
- Primary Topic
- Circadian rhythm and melatonin
- Type
- article
- Field-Weighted Citation Impact
- 0.00