Enlightening the "Spirit Molecule": Photomodulation of the 5-HT2A Receptor by a Light-Controllable N,N-Dimethyltryptamine Derivative.

Classical psychedelics alter consciousness by activating the 5-HT2A receptor in the brain, but the precise mechanism is not fully understood. To study this receptor's signaling with high spatiotemporal precision, researchers designed photoswitchable ligands based on the psychedelic N,N-dimethyltryptamine (DMT). By incorporating the DMT-indole ring into a photoswitchable system, they created red-shifted ligands operable by visible light. Among these azo-DMTs, compound 2h (Photo-DMT) stands out: its cis isomer shows DMT-like activity, while the trans isomer acts as a weak partial agonist. This cis-on efficacy switch expands the pharmacological toolbox for investigating the complex signaling of the 5-HT2A receptor.

Study at a glance

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.