Enlightening the "Spirit Molecule": Photomodulation of the 5-HT2A Receptor by a Light-Controllable N,N-Dimethyltryptamine Derivative.
Hubert Gerwe, Feng He, Eline Pottie, Christophe P Stove, Michael Decker
Angewandte Chemie International Edition June 27, 2022 DOI: 10.1002/anie.202203034 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | Serotonin 5-MeO-DMT DMT |
| Keywords | Phenylazoindoles Photopharmacology Psychedelics Tryptamines |
| Citations | 21 |
| Key points | Proposes that a photoswitchable ligand called Photo-DMT, which is active as an agonist in its cis form and a weak partial agonist in its trans form, can serve as a tool to investigate 5-HT2A receptor signaling mechanisms. |
Abstract
Classical psychedelics are a group of hallucinogens which trigger non-ordinary states of consciousness through activation of the 5-HT2A receptor (5-HT2A R) in the brain. However, the exact mechanism of how 5-HT2A R agonism alters perception remains elusive. When studying receptor signaling, tools which work at the same spatiotemporal resolution as the receptor are exceptionally useful. To create such a tool, we designed a set of photoswitchable ligands based on the classical psychedelic N,N-dimethyltryptamine (DMT). By incorporation of the DMT-indole ring into the photoswitchable system, we obtained red-shifted ligands which can be operated by visible light. Among these azo-DMTs, compound 2 h ("Photo-DMT") stands out as its cis isomer exhibits DMT like activity while the trans isomer acts as weak partial agonist. Such a cis-on "efficacy switch" substantially expands the pharmacological toolbox to investigate the complex mechanisms of 5-HT2A R signaling.
Comparable studies
Other theoretical and historical papers on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| When the Endogenous Hallucinogenic Trace AmineN,N-Dimethyltryptamine Meets the Sigma-1 Receptor | 2009 | Theoretical or philosophical paper | |
| Analytical chemistry of synthetic routes to psychoactive tryptamines : Part I. Characterisation of the Speeter and Anthony synthetic route to 5-methoxy-N,N-diisopropyltryptamine using ESI-MS-MS and ESI-TOF-MS | 2004 | Theoretical or philosophical paper | |
| Conformational, spectroscopic and nonlinear optical properties of biologically active N,N-dimethyltryptamine molecule: a theoretical study. | 2014 | Theoretical or computational study | |
| Simple syntheses of lespedamine and 5-bromo-n,n-dimethyltryptamine based on 1-hydroxyindole chemistry | 1995 | Theoretical or philosophical paper | |
| 5-Methoxy-N,N-dimethyltryptamine: An Ego-Dissolving Endogenous Neurochemical Catalyst of Creativity | 2019 | Theoretical or philosophical paper |
Citations in the library
Cited by 3
- The Bright Side of Psychedelics: Latest Advances and Challenges in Neuropharmacology International Journal of Molecular Sciences January 10, 2023
- Design, Synthesis, and In Vitro Characterization of a Tryptamine-Based Visible-Light Photoswitchable 5-HT2AR Ligand Showing Efficacy Preference for β-Arrestin over Mini-Gq. Journal of Medicinal Chemistry June 18, 2025
- Computational design of an improved photoswitchable psychedelic based on light absorption, membrane permeation and protein binding. Physical chemistry chemical physics : PCCP September 18, 2025
Cites 10
- Human Psychopharmacology of Hoasca, A Plant Hallucinogen Used in Ritual Context in Brazil The Journal of Nervous and Mental Disease February 1, 1996
- Neuropharmacology of N,N-dimethyltryptamine Brain Research Bulletin April 30, 2016
- N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function Frontiers in Neuroscience August 6, 2018
- Prehistoric peyote use: alkaloid analysis and radiocarbon dating of archaeological specimens of Lophophora from Texas. Journal of Ethnopharmacology October 3, 2005
- Investigation of the Structure–Activity Relationships of Psilocybin Analogues ACS Pharmacology & Translational Science December 14, 2020
and 5 more in the library