The structural diversity of psychedelic drug actions revealed

Ryan H. Gumpper (), Manish K. Jain, Kuglae Kim, Renhong Sun, Ning Sun, Zhongli Xu, Jeffrey F. DiBerto, Brian E. Krumm, Nicholas J. Kapolka, H. Ümit Kaniskan, David E. Nichols, Jian Jin, Jonathan F. Fay and Bryan L. Roth ()
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Ryan H. Gumpper: University of North Carolina at Chapel Hill School of Medicine
Manish K. Jain: University of North Carolina at Chapel Hill School of Medicine
Kuglae Kim: Yonsei University
Renhong Sun: Icahn School of Medicine at Mount Sinai
Ning Sun: Icahn School of Medicine at Mount Sinai
Zhongli Xu: Icahn School of Medicine at Mount Sinai
Jeffrey F. DiBerto: University of North Carolina at Chapel Hill School of Medicine
Brian E. Krumm: University of North Carolina at Chapel Hill School of Medicine
Nicholas J. Kapolka: LLC
H. Ümit Kaniskan: Icahn School of Medicine at Mount Sinai
David E. Nichols: University of North Carolina
Jian Jin: Icahn School of Medicine at Mount Sinai
Jonathan F. Fay: University of Maryland Baltimore
Bryan L. Roth: University of North Carolina at Chapel Hill School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT2A receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT2A activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57956-7

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DOI: 10.1038/s41467-025-57956-7

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