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Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design. J Med Chem 2025 Oct 09;68(19):20619-20635

Date

09/26/2025

Pubmed ID

40997862

Pubmed Central ID

PMC12713736

DOI

10.1021/acs.jmedchem.5c01855

Scopus ID

2-s2.0-105018334639 (requires institutional sign-in at Scopus site)

Abstract

With a resurgence in interest in psychedelics as rapid-acting and durable neuroplastic therapies, there is a critical need to develop more selective 5-HT2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT2A over the closely related 5-HT2C receptor can be leveraged using structure-based design to target residue L1232.53 in transmembrane 2 (TM2) of the extended binding pocket by increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. Furthermore, we comprehensively confirm selectivity at 5-HT2C RNA editing isoforms, TM2 reciprocal 5-HT2A and 5-HT2C mutants, and mouse 5-HT2A and 5-HT2C orthologs, to form a complete profile for highly selective 5-HT2A agonists to date. Using a combination of structure-activity relationships, molecular docking, and mouse head-twitch response assays, we show that 5-HT2A-selective agonists can be rationally designed to improve 5-HT2A target engagement, further advancing the study into the neurobiological mechanisms of psychedelic effects.

Author List

Fenske TG, McKee JL, Cavalco NG, Schalk SS, Bonniwell EM, Lammers JC, Shacham N, Cuccurazzu B, Halberstadt AL, McCorvy JD

Authors

Emma M. Bonniwell Postdoctoral Researcher in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Tyler G. Fenske PhD Postdoctoral Researcher 3 in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Drug Design
Drug Discovery
HEK293 Cells
Humans
Mice
Molecular Docking Simulation
Receptor, Serotonin, 5-HT2A
Receptor, Serotonin, 5-HT2C
Serotonin 5-HT2 Receptor Agonists
Structure-Activity Relationship