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 Stove, Michael Decker
Angewandte Chemie (International ed. in English) June 27, 2022 Peer reviewed DOI: 10.1002/anie.202203034 via PubMed
Summary
A new set of photoswitchable ligands, based on the classical psychedelic DMT, has been developed to study how 5-HT2A receptor activation alters perception. Among these, compound 2h, dubbed 'Photo-DMT', can switch between two forms: the cis isomer shows DMT-like activity, while the trans isomer acts as a weak partial agonist. This innovation provides a valuable tool for exploring the mechanisms behind 5-HT2A receptor signaling.
Study at a glance
| Key finding | The compound 2h ('Photo-DMT') exhibits a unique cis-on efficacy switch that enhances the ability to study 5-HT2A receptor signaling. |
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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.