Structure-based design of subtype-selective psychedelic analogs.

Cryo-EM structures reveal key residue differences enabling design of 5-HT 2A receptor-selective psychedelics, avoiding 5-HT 2B receptor activation.

• Why it matters: Selective activation of 5-HT 2A R over 5-HT 2B R is crucial to minimize cardiac risks associated with psychedelics, addressing safety concerns in neuropsychiatric treatments.
• What they did: The team determined the cryo-EM structure of 5-HT 2A R, analyzed orthosteric binding pockets, and developed a pharmacophore model guiding the synthesis of compounds that selectively target 5-HT 2A R.
• The result: Two compound series were created that activate 5-HT 2A R while antagonizing 5-HT 2B R, with selected compounds showing antidepressant-like effects in animals, paving the way for safer psychedelic therapies.