The structural diversity of psychedelic drug actions revealed
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 effects.
Authors
- Bryan L. Roth (ORCID: https://orcid.org/0000-0002-0561-6520)
- Ning Sun (ORCID: https://orcid.org/0000-0003-4374-6489)
- H. Ümit Kanıskan (ORCID: https://orcid.org/0000-0001-5327-832X)
- Kuglae Kim (ORCID: https://orcid.org/0000-0001-6660-8738)
- Nicholas J. Kapolka (ORCID: https://orcid.org/0000-0003-2223-8207)
- Jian Jun Jin (ORCID: https://orcid.org/0000-0002-2387-3862)
- Renhong Sun (ORCID: https://orcid.org/0000-0003-2891-0551)
- Ryan H. Gumpper (ORCID: https://orcid.org/0000-0003-1309-3069)
- Zhongli Xu (ORCID: https://orcid.org/0000-0001-6843-6212)
- Jonathan F. Fay (ORCID: https://orcid.org/0000-0003-1822-2384)
- Jeffrey F. DiBerto (ORCID: https://orcid.org/0000-0002-8227-2071)
- B. Krumm (ORCID: https://orcid.org/0000-0001-6039-4767)
- Manish K. Jain (ORCID: https://orcid.org/0000-0001-8173-3326)
- David E. Nichols
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Maryland, Baltimore (US)
- Yonsei University (KR)
- Zen Bio (United States) (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-19
- DOI
- https://doi.org/10.1038/s41467-025-57956-7
- Citations
- 25
- Primary Topic
- Psychedelics and Drug Studies
- Type
- article
- Field-Weighted Citation Impact
- 57.67
Funders
- Defense Advanced Research Projects Agency
- National Institute on Drug Abuse