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Structure paper

TitleStructural pharmacology and therapeutic potential of 5-methoxytryptamines.
Journal, issue, pagesNature, Year 2024
Publish dateMay 8, 2024
AuthorsAudrey 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 / Daniel Wacker /
PubMed AbstractPsychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their ...Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT 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, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT 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 agonists. We show that a 5-HT-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-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
External linksNature / PubMed:38720072
MethodsEM (single particle)
Resolution2.62 - 2.94 Å
Structure data

29560

8fy8

EMDB-29560, PDB-8fy8:
5-MeO-DMT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.79 Å

29571

8fye

EMDB-29571, PDB-8fye:
4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.85 Å

29585

8fyl

EMDB-29585, PDB-8fyl:
Vilazodone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.94 Å

29597

8fyt

EMDB-29597, PDB-8fyt:
LSD-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.64 Å

29599

8fyx

EMDB-29599, PDB-8fyx:
Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Method: EM (single particle) / Resolution: 2.62 Å

Chemicals


ChemComp, No image

ChemComp-YFW:
Unknown entry

ChemComp-J40:
[(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE


ChemComp, No image

ChemComp-YGH:
Unknown entry

ChemComp-YG7:
5-{4-[4-(5-cyano-1H-indol-3-yl)butyl]piperazin-1-yl}-1-benzofuran-2-carboxamide / medication*YM / Vilazodone

ChemComp-7LD:
(8alpha)-N,N-diethyl-6-methyl-9,10-didehydroergoline-8-carboxamide / Lysergic acid diethylamide


ChemComp, No image

ChemComp-YLX:
Unknown entry

Source
  • Escherichia coli, Homo sapiens
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / GPCR Signaling Complex / Serotonin Receptor

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