The structural diversity of psychedelic drug actions revealed
DiBerto, J. F., Fay, J. F., Gumpper, R. H., Jain, M. K., Jin, J., Kaniskan, H. Ü., Kapolka, N., Kim, K., Krumm, B. E., Nichols, D. E., Roth, B. L., Sun, N., Sun, R., Xu, Z.
This study presents seven cryo-electron microscopy (cryo-EM) structures showing how different classes of psychedelic and non-psychedelic compounds interact with the serotonin (5-HT) 2A receptor-the primary target for classical psychedelics' therapeutic effects-revealing both shared and distinct binding patterns that could guide the development of new therapeutic compounds with improved side effect profiles.
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 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.