Structural Pharmacology of Bufotenine Derivatives in Activating the 5-HT 1A Receptor for Therapeutic Potential in Depression and Anxiety
Shujie Li, Shu-Jie Li, Qingning Yuan, Wen‐yuan Wu, Adriaan C.i.t.l. Tan, Zhihan Chen, Duo Chen, Hong Shan, Quincy Chu, Wenhao Hu, Kaichun Wu, Tao Liu, Deguang Wang, Li Hou, Jia Duan, Jin‐ao Duan, H. Eric Xu
Research 2025 DOI: 10.34133/research.0987 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | 5-OH-DMT 5-hydroxy-N N |
| Topics | Anxiety Depression Serotonin |
| Key findings | 5-OH-DMT and 5-MeO-DMT are promising antidepressant and anxiolytic candidates that engage the 5-HT1A receptor with distinct binding conformations, while minimizing hallucinogenic liability through reduced 5-HT2A activation. |
Abstract
The 5-HT 1A receptor is a critical target in the treatment of depression and anxiety. Bufotenine derivatives, such as 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT), 5-hydroxy- N , N -dimethyltryptamine (5-OH-DMT), and 5-hydroxy- N , N , N -dimethyltryptamine—derived from traditional Chinese medicine—have shown antidepressant potential. However, the structural basis of their interaction with 5-HT 1A and their pharmacological profiles remain incompletely understood. This study investigated bufotenine derivatives acting on multiple serotonin receptors, highlighting 5-HT 1A as a key mediator of antidepressant effects while recognizing 5-HT 2A 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 1A 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 1A 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 1A 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 1A .
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
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and 20 more in the library