Discovery of Highly Selective 5-HT_2A Agonists Using Structure-Guided Design.

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-HT_2A agonists to investigate the basic neurobiological mechanisms of psychedelics. Here, we show that selectivity for 5-HT_2A over the closely related 5-HT_2C receptor can be leveraged using structure-based design to target residue L123^2.53 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-HT_2C RNA editing isoforms, TM2 reciprocal 5-HT_2A and 5-HT_2C mutants, and mouse 5-HT_2A and 5-HT_2C

SUBMITTER: Fenske TG 

PROVIDER: S-EPMC12713736 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature