Humans have made use of the “mind extending” properties of psychedelic compounds like mescaline, psilocibin and N,N-dimethyltryptamine (DMT) since ancient times. These classical psychedelics trigger non-ordinary states of consciousness by agonism at a serotonin receptor subtype (5-HT2A receptor) in the brain. However, the exact mechanism of how 5-HT2A receptor agonism alters our perception remains elusive. To expand the pharmacological toolbox for the investigation of 5-HT2A receptor signaling, we designed and synthesized a set of photoswitchable ligands based on DMT. By incorporation of the DMT-indole into the photoswitchable system we not only obtained slightly red-shifted photoswitchable ligands which can be operated with visible light but also extended the structure activity relationships (SARs) for the tryptamine class of psychedelics. Among our set of azo-DMTs, 5-(4-MeO)-azo-DMT stands out as its cis isomer exhibits DMT like activity while the trans isomer acts as very weak partial agonist only. Such a “cis-on" efficacy switch can effectively turn the receptor into an artificial photoreceptor which allows investigation of the complex mechanisms of 5-HT2A receptor signaling events with a substantially increased spatiotemporal resolution.

Enlightening the “spirit molecule” – development of a “cis-on” efficacy switch at the 5-HT2A receptor using N,N-dimethyltryptamine as lead structure

ACS Spring 2022

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