Peer-reviewed articleOpen access

Mechanistic Basis for 5-HT2AR Over 5-HT2BR Activation.

Tang L, Ji X, Wang Y, Cao D, Li H, He L iD, Cheng J iD, Wang S iD

Nature communicationsSep 17, 2026License: open accessChina0 citationsDOI: 10.1038/s41467-026-77659-x

Abstract

Selective 5-HT2AR agonism without 5-HT2BR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HT2AR and 5-HT2BR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we design derivatives across tryptamine and phenethylamine scaffolds that integrate SEP and EBP engagement with scaffold modification to reinforce 5-HT2AR activation while limiting 5-HT2BR activity. Cryo-EM structures of 5-HT2AR and 5-HT2BR bound to IHCH-2330, a selective 5-HT2AR agonist and 5-HT2BR antagonist, confirm the design principle. These findings show differential activation mechanisms between 5-HT2AR and 5-HT2BR and provide a rational framework for engineering safer, functionally selective serotonergic compounds, mitigating 5-HT2BR-mediated side effects while preserving therapeutic efficacy.

Topics & conditions

Detected automatically by Psychedelic Commons from the title and abstract, not labels from the source. They may be incomplete.

Psychedelics

View paper Full text (PDF)

Psychedelic Commons aggregates metadata from open sources and links back to the original. Rights remain with the authors and publishers. Something wrong with this record? Report a problem.