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The structural diversity of psychedelic drug actions revealed

Author

Listed:
  • Ryan H. Gumpper

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina)

  • 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
    LLC)

  • 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
    University of North Carolina)

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.

Suggested Citation

  • 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 & Jonat, 2025. "The structural diversity of psychedelic drug actions revealed," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57956-7
    DOI: 10.1038/s41467-025-57956-7
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