Enlightening the “Spirit Molecule”: Photomodulation of the 5‐HT(2A) Receptor by a Light‐Controllable N,N‐Dimethyltryptamine Derivative

Classical psychedelics are a group of hallucinogens which trigger non‐ordinary states of consciousness through activation of the 5‐HT(2A) receptor (5‐HT(2A)R) in the brain. However, the exact mechanism of how 5‐HT(2A)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‐HT(2A)R signaling.