Designing psychedelic-like compounds that selectively target specific brain receptor types

The cryo-EM structure of 5-HT2A receptor was determined to inform the design of 5-HT2A receptor-selective agonists.

• Classical psychedelics activate the serotonin 2A receptor, which is linked to their therapeutic effects.
• Concurrent activation of the serotonin 2B receptor is associated with serious safety concerns, such as cardiac valvulopathy.
• A comparative structural analysis of the binding pockets of the 5-HT2A and 5-HT2B receptors was performed to identify differences.
• A trigonal pharmacophore model was developed to guide the design of selective compounds that activate 5-HT2A while antagonizing 5-HT2B.
• Two series of compounds were synthesized that selectively activate 5-HT2A receptors and inhibit 5-HT2B activity.
• Selected compounds demonstrated antidepressant-like effects in animal models.

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