Structural insights into tryptamine psychedelics: The role of hydroxyl indole ring site in 5-HT2A receptor activation and psychedelic-like activity.
Miyuan Zhang, Yuefeng Yang, Zhishuai Yang, Xin Wen, Cong Zhang, Peng Xiao, Yibo Wang, Jinpeng Sun, Hongshuang Wang, Xiaohui Wang
European journal of medicinal chemistry January 5, 2025 DOI: 10.1016/j.ejmech.2024.117049 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | psilocin bufotenine 6-OH-DMT 7-OH-DMT |
| Topics | Psilocybin Serotonin |
| Keywords | Molecular structure Biochemistry Hydroxyl indole ring Molecular dynamics simulation Psychedelic-like activity Psychedelics Pharmacology |
| Citations | 10 |
| Key findings | Psilocin and bufotenine, with hydroxyl groups at the 4th and 5th indole ring positions respectively, exhibit higher 5-HT2A receptor agonistic activity and psychedelic-like effects than analogs with the hydroxyl group at the 6th or 7th position, due to specific hydrogen bonding and salt bridge interactions with residues L229 and D155. |
Abstract
Recent advancements in the study of mushroom-derived tryptamines, particularly psilocybin and its metabolite psilocin, highlight their unique psychedelic properties and potential therapeutic applications, especially for mental health conditions like depression. This study examines how the position of the hydroxyl group on the indole ring affects the 5-HT2A receptor activity and psychedelic-like effects of psilocin analogs. Chemically synthesized psilocin (1) and its analogs bufotenine (2), 6-OH-DMT (3), and 7-OH-DMT (4) were assessed for 5-HT2A receptor agonistic activity using the Gαq-Gγ dissociation bioluminescence resonance energy transfer (BRET) assay and for psychedelic-like effects through the head-twitch response assay. Results show that compounds with hydroxyl group at the 4th and 5th positions exhibit significantly higher 5-HT2A agonistic and psychedelic-like activities than those with hydroxyl group at the 6th and 7th positions. Funnel metadynamics simulations revealed that psilocin (1) and bufotenine (2) have lower binding free energies, correlating with experimental data. Analysis of the simulation trajectories reveals that the formation of a hydrogen bond with residue L229 is crucial for guiding psilocin (1) and bufotenine (2) into the 5-HT2AR binding site. In contrast, analogs 3 and 4, which lack this interaction, fail to be directed into the orthosteric site. Furthermore, psilocin (1) and bufotenine (2) establish a stable salt bridge and hydrogen bond with residue D155. These interactions are more stable compared to those formed by ligands 3 and 4, contributing to the latter's poor 5-HT2AR activities. These findings underscore the critical role of the hydroxyl group position on the indole ring in modulating 5-HT2A receptor activity and the corresponding psychedelic-like effects, offering valuable insights for the development of targeted therapeutics.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 6
- Low, non-psychedelic doses of psilocybin as a novel treatment for MASLD, obesity and type 2 diabetes via 5-HT2B receptor-dependent mechanisms Pharmacological Research December 29, 2025
- Psychedelic experiences elicited by serotonergic psychedelics: Molecular mechanisms and functional connectivity changes in the brain Neuroscience & Biobehavioral Reviews December 16, 2025
- Psychedelic Drugs Rediscovered-In Silico Study of Potential Fetal Exposure to Analogues of Psychedelic Drugs During Pregnancy. Molecules January 8, 2026
- The Medial Prefrontal Cortex Modulates Psychedelic-like Effects of Psilocin ACS Pharmacology & Translational Science July 8, 2025
- Rapid, open-source, and automated quantification of the head twitch response in C57BL/6J mice using DeepLabCut and Simple Behavioral Analysis bioRxiv Preprint Server April 28, 2025
and 1 more in the library
Cites 18
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology December 1, 2011
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 13 more in the library