Structural pharmacology and therapeutic potential of 5-methoxytryptamines.

Autor: Warren AL; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Lankri D; Department of Chemistry, Columbia University, New York, NY, USA., Cunningham MJ; Department of Chemistry, Columbia University, New York, NY, USA., Serrano IC; Department of Chemistry, Columbia University, New York, NY, USA., Parise LF; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Kruegel AC; Department of Chemistry, Columbia University, New York, NY, USA., Duggan P; Department of Chemistry, Columbia University, New York, NY, USA., Zilberg G; Zuckerman Institute of Mind, Brain, Behavior, Columbia University, New York, NY, USA., Capper MJ; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Havel V; Department of Chemistry, Columbia University, New York, NY, USA., Russo SJ; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sames D; Department of Chemistry, Columbia University, New York, NY, USA. ds584@columbia.edu.; Zuckerman Institute of Mind, Brain, Behavior, Columbia University, New York, NY, USA. ds584@columbia.edu., Wacker D; Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. daniel.wacker@mssm.edu.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. daniel.wacker@mssm.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jun; Vol. 630 (8015), pp. 237-246. Date of Electronic Publication: 2024 May 08.
DOI: 10.1038/s41586-024-07403-2
Abstrakt: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders 1-3 . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT 2A (ref. 4 ). However, 5-HT 1A also plays a part in the behavioural effects of tryptamine hallucinogens 5 , particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads 6 . Although 5-HT 1A is a validated therapeutic target 7,8 , little is known about how psychedelics engage 5-HT 1A 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-HT 1A , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT 1A and 5-HT 2A enable the characterization of molecular determinants of 5-HT 1A 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-HT 1A agonists. We show that a 5-HT 1A -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-HT 1A -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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