Gumpper Ryan H, Jain Manish K, Kim Kuglae, Sun Renhong, Sun Ning, Xu Zhongli, DiBerto Jeffrey F, Krumm Brian E, Kapolka Nicholas J, Kaniskan H Ümit, Nichols David E, Jin Jian, Fay Jonathan F, Roth Bryan L
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.
Nat Commun. 2025 Mar 19;16(1):2734. doi: 10.1038/s41467-025-57956-7.
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 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 receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.
目前，在探索经典迷幻剂用于治疗抑郁症、成瘾、焦虑症、丛集性头痛及许多其他神经精神疾病方面正重新兴起一股热潮。这些化合物的一个生物学靶点，也是其治疗作用的一个假设靶点，是5-羟色胺（5-HT）血清素受体。在此，我们展示了7个冷冻电镜结构，涵盖了迷幻剂和非迷幻剂激动剂的所有主要化合物类别，包括一种偏向β-抑制蛋白的化合物RS130-180。确定各种迷幻剂与5-HT受体之间的分子相互作用揭示了所研究的迷幻剂化学类型中的共同和独特基序。这些发现有助于对5-HT激活有更广泛的机制理解，这可以促进具有潜在治疗效用且副作用更少的新型化学类型的开发。
