Structural pharmacology and therapeutic potential of 5-methoxytryptamines

Audrey L. Warren, David Lankri, Michael J. Cunningham, Inis C. Serrano, Lyonna F. Parise, Andrew C. Kruegel, Priscilla Duggan, Gregory Zilberg, Michael J. Capper, Vaclav Havel, Scott J. Russo, Dalibor Sames () and Daniel Wacker ()
Additional contact information
Audrey L. Warren: Icahn School of Medicine at Mount Sinai
David Lankri: Columbia University
Michael J. Cunningham: Columbia University
Inis C. Serrano: Columbia University
Lyonna F. Parise: Icahn School of Medicine at Mount Sinai
Andrew C. Kruegel: Columbia University
Priscilla Duggan: Columbia University
Gregory Zilberg: Columbia University
Michael J. Capper: Icahn School of Medicine at Mount Sinai
Vaclav Havel: Columbia University
Scott J. Russo: Icahn School of Medicine at Mount Sinai
Dalibor Sames: Columbia University
Daniel Wacker: Icahn School of Medicine at Mount Sinai

Nature, 2024, vol. 630, issue 8015, 237-246

Abstract: Abstract Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders1–3. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. 4). However, 5-HT1A also plays a part in the behavioural effects of tryptamine hallucinogens5, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads6. Although 5-HT1A is a validated therapeutic target7,8, little is known about how psychedelics engage 5-HT1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT1A and 5-HT2A enable the characterization of molecular determinants of 5-HT1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT1A agonists. We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

Date: 2024
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DOI: 10.1038/s41586-024-07403-2

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