Discovery of Highly Selective 5-HT2A Agonists Using Structure-Guided Design

  • J Med Chem. 2025 Oct 9;68(19):20619-20635. doi: 10.1021/acs.jmedchem.5c01855.
Tyler G Fenske  1 ,  John L McKee  1 ,  Natalie G Cavalco  1 ,  Serena S Schalk  1 ,  Emma M Bonniwell  1 ,  Josie C Lammers  1 ,  Naomi Shacham  2 ,  Bruna Cuccurazzu  2 ,  Adam L Halberstadt  2  3 ,  John D McCorvy  1
Affiliations
  • 1. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.
  • 2. Department of Psychiatry, University of California San Diego, La Jolla, California 92093, United States.
  • 3. Research Service, VA San Diego Healthcare System, San Diego, California 92108, United States.
PMID: 40997862 DOI: 10.1021/acs.jmedchem.5c01855
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.

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