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<p>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-HT<sub>2A</sub> 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-HT<sub>2A</sub> receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT<sub>2A</sub> activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side&#xa0;effects.</p>

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The structural diversity of psychedelic drug actions revealed

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年3月19日

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  • 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,
  • Bryan L. Roth

摘要

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.