Structural Superimposition

Abstact

Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HT(2A)R), offering promise as transformative treatments for neuropsychiatric disorders. However, their concurrent activation of 5-HT(2B)R-associated with cardiac valvulopathy-raises serious safety concerns, underscoring the need for subtype-selective psychedelics. To address this, we determine the cryo-EM structure of 5-HT(2A)R and perform a comparative structural analysis of the orthosteric binding pockets (OBPs) of 5-HT(2A)R and 5-HT(2B)R. Guided by key residue differences, we develop a trigonal pharmacophore model to inform the design of 5-HT(2A)R-selective agonists that avoid 5-HT(2B)R activation. Using this model, we design and synthesize two compound series that selectively activate 5-HT(2A)R while antagonizing 5-HT(2B)R. Molecular basis of subtype selectivity is confirmed by five additional cryo-EM structures of receptor-ligand complexes. Selected compounds also exhibit antidepressant-like efficacy in animal models. Our findings provide a strategy for the development of safer, subtype-selective psychedelic analogs with therapeutic potential.