The structural diversity of psychedelic drug actions revealed

作者：Ryan H. Gumpper, Manish K. Jain, Kuglae Kim, Renhong Sun, Ning Sun, Zhongli Xu, Jeffrey F. DiBerto, B. Krumm, Nicholas J. Kapolka, H. Ümit Kanıskan, David E. Nichols, Jian Jin, Jonathan F. Fay, Bryan L. Roth · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-57956-7 · 被引用次数：33 · 研究领域：Psychedelics and Drug Studies、Chemical synthesis and alkaloids、Tryptophan and brain disorders

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. The authors present 7 cryo-EM structures of hallucinogenic and non-hallucinogenic compounds across multiple chemotypes bound to the 5-HT2A receptor, shedding light onto ligand specificity and signaling bias.