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Structure paper

TitleStructural Pharmacology of Bufotenine Derivatives in Activating the 5-HT Receptor for Therapeutic Potential in Depression and Anxiety.
Journal, issue, pagesResearch (Wash D C), Vol. 8, Page 0987, Year 2025
Publish dateDec 23, 2025
AuthorsShu-Jie Li / Qing-Ning Yuan / Wen-Yuan Wu / Zhi-Han Chen / Duo Chen / Hong Shan / Qin-Yu Chu / Wen Hu / Kai Wu / Tao Liu / Yu-Yu Zhu / Li Hou / Jing Zhou / Jia Duan / Jin-Ao Duan / H Eric Xu / Hong-Yue Ma /
PubMed AbstractThe 5-HT receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-,-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-,-dimethyltryptamine (5-OH-DMT) ...The 5-HT receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy-,-dimethyltryptamine (5-MeO-DMT), 5-hydroxy-,-dimethyltryptamine (5-OH-DMT), and 5-hydroxy-,,-dimethyltryptamine-derived from traditional Chinese medicine-have shown antidepressant potential. However, the structural basis of their interaction with 5-HT and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT as a key mediator of antidepressant effects while recognizing 5-HT as primarily responsible for hallucinogenic outcomes, to identify candidates with therapeutic efficacy but reduced hallucinogenic liability. We determined the cryo-electron microscopy structures of 5-HT bound to selected bufotenine derivatives. Functional assays in mice, including behavioral tests and receptor activation studies, were used to evaluate the antidepressant of each compound. Structural analysis revealed that all bufotenine derivatives engage conserved motifs within the 5-HT binding pocket, with 5-OH-DMT displaying a distinct interaction pattern. Behavioral assays showed that 5-OH-DMT and 5-MeO-DMT retained strong antidepressant and anxiolytic effects. These pharmacological differences correlate with their unique receptor binding conformation. This study delineated the structural pharmacology of bufotenine derivatives at the 5-HT receptor, identifying 5-OH-DMT and 5-MeO-DMT as promising antidepressant and anxiolytic candidates. The findings establish a molecular framework for the development of next-generation nonhallucinogenic therapeutics aimed at 5-HT.
External linksResearch (Wash D C) / PubMed:41446874 / PubMed Central
MethodsEM (single particle)
Resolution2.54 - 2.63 Å
Structure data

62593

9kvg

EMDB-62593, PDB-9kvg:
A Cryo_EM structure of 5_HT1A complex with 5-Meo-DMT
Method: EM (single particle) / Resolution: 2.63 Å

62594

9kvh

EMDB-62594, PDB-9kvh:
A Cryo_EM structure of 5_HT1A complex with TMT
Method: EM (single particle) / Resolution: 2.59 Å

62595

9kvi

EMDB-62595, PDB-9kvi:
A Cryo_EM structure of 5_HT1A complex with DMT
Method: EM (single particle) / Resolution: 2.54 Å

Chemicals


ChemComp, No image

ChemComp-YFW:
Unknown entry

ChemComp-CHO:
GLYCOCHENODEOXYCHOLIC ACID / detergent*YM

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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-HOH:
WATER

PDB-1eg9:
NAPHTHALENE 1,2-DIOXYGENASE WITH INDOLE BOUND IN THE ACTIVE SITE.

ChemComp-CLR:
CHOLESTEROL

PDB-1eg8:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GPCR / 5_HT1A

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