Translated from our German original by AI. The German text was researched, written, and edited by the Psychedelia Foundation team and remains the authoritative version.
A research team has presented a structure-based approach to developing new psychedelic analogs that selectively activate the serotonin 5-HT₂A receptor while avoiding activation of the related 5-HT₂B receptor. The study appeared in Nature Communications.
Classic psychedelics produce their central effects largely through the 5-HT₂A receptor. Activation of the 5-HT₂B receptor, by contrast, is treated as a safety concern, because it has been linked to changes in the heart valves. The researchers therefore examined the structural differences between the two receptor subtypes with a view to using them for more selective drug development.
They first determined the structure of the 5-HT₂A receptor by cryo-electron microscopy and compared its orthosteric binding pocket with that of the 5-HT₂B receptor. Characteristic differences between the two led them to a trigonal pharmacophore model, which then guided the design and synthesis of two series of new compounds.
The compounds tested selectively activated the 5-HT₂A receptor while acting as antagonists at the 5-HT₂B receptor. Five further cryo-EM structures of receptor-ligand complexes confirmed the structural basis of this selectivity.
Selected compounds also produced behavioral effects in preclinical animal models that are interpreted as antidepressant-like. Those results are not the same as evidence of an antidepressant effect in humans. A real safety advantage from reduced 5-HT₂B activation has likewise not been shown clinically so far.
What the work offers above all is a structure-based route to 5-HT₂A-selective psychedelic drug candidates. Deliberately avoiding 5-HT₂B activation could, in the authors’ view, help improve the safety profile of future compounds. Whether the compounds they developed actually produce psychedelic effects, work therapeutically, and carry a more favorable safety profile in humans will have to be settled in further preclinical and clinical research.
