The structural diversity of psychedelic drug actions revealed.

BeobachtungsstudiePubMed13. Mai 2025PMID: 40108183 DOI

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 -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.

Autoren (14)

LeadDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. rgumpper@email.unc.edu.

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, Korea.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Zhongli XuMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Jeffrey F DiBertoDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

Brian E KrummDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.

Nicholas J KapolkaEvE Bio, LLC, Durham, NC, USA.

H Ümit KaniskanMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

David E NicholsDivision of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Jian JinMount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences, Oncological Sciences and Neuroscience, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Jonathan F FayDepartment of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA.

Bryan L RothDepartment of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA. bryan_roth@med.unc.edu.

MeSH Terms

HallucinogensHumansReceptor, Serotonin, 5-HT2ACryoelectron MicroscopySerotonin 5-HT2 Receptor Agonistsbeta-Arrestins

Metadaten

StudientypBeobachtungsstudie

QuellePubMed

Publikationsdatum13. Mai 2025

Zitierungen0

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