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Structural pharmacology and therapeutic potential of 5-methoxytryptamines.
- Source :
-
Nature [Nature] 2024 Jun; Vol. 630 (8015), pp. 237-246. Date of Electronic Publication: 2024 May 08. - Publication Year :
- 2024
-
Abstract
- Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders <superscript>1-3</superscript> . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT <subscript>2A</subscript> (ref. <superscript>4</superscript> ). However, 5-HT <subscript>1A</subscript> also plays a part in the behavioural effects of tryptamine hallucinogens <superscript>5</superscript> , particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads <superscript>6</superscript> . Although 5-HT <subscript>1A</subscript> is a validated therapeutic target <superscript>7,8</superscript> , little is known about how psychedelics engage 5-HT <subscript>1A</subscript> 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 <subscript>1A</subscript> , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT <subscript>1A</subscript> and 5-HT <subscript>2A</subscript> enable the characterization of molecular determinants of 5-HT <subscript>1A</subscript> 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 <subscript>1A</subscript> agonists. We show that a 5-HT <subscript>1A</subscript> -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 <subscript>1A</subscript> -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Humans
Male
Mice
Cryoelectron Microscopy
Hallucinogens
Lysergic Acid Diethylamide chemistry
Lysergic Acid Diethylamide pharmacology
Models, Molecular
Serotonin Receptor Agonists chemistry
Serotonin Receptor Agonists pharmacology
Serotonin Receptor Agonists therapeutic use
Structure-Activity Relationship
5-Methoxytryptamine analogs & derivatives
5-Methoxytryptamine chemistry
5-Methoxytryptamine pharmacology
5-Methoxytryptamine therapeutic use
Anti-Anxiety Agents chemistry
Anti-Anxiety Agents pharmacology
Anti-Anxiety Agents therapeutic use
Antidepressive Agents chemistry
Antidepressive Agents pharmacology
Antidepressive Agents therapeutic use
Methoxydimethyltryptamines chemistry
Methoxydimethyltryptamines pharmacology
Methoxydimethyltryptamines therapeutic use
Receptor, Serotonin, 5-HT1A chemistry
Receptor, Serotonin, 5-HT1A genetics
Receptor, Serotonin, 5-HT1A metabolism
Receptor, Serotonin, 5-HT1A ultrastructure
Receptor, Serotonin, 5-HT2A chemistry
Receptor, Serotonin, 5-HT2A genetics
Receptor, Serotonin, 5-HT2A metabolism
Receptor, Serotonin, 5-HT2A ultrastructure
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 630
- Issue :
- 8015
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 38720072
- Full Text :
- https://doi.org/10.1038/s41586-024-07403-2