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 ed. in English) 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.