Psychedelic-Inspired Drug Discovery Using an Engineered Biosensor

The myriad conformations of a G protein-coupled receptors induced by ligands are critical for determining signaling cascades associated with distinct functional and behavioral consequences. For example, 5-hydroxytryptamine 2A receptors (5-HT2AR) are the target for classic hallucinogens, atypical antipsychotics, and plasticity-promoting psychoplastogens. However, current methods are inadequate for directly assessing specific 5-HT2AR conformations. Here, we developed psychLight, a genetically-encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight reports behaviorally-relevant serotonin release and 5-HT2AR conformations induced by serotonergic hallucinogens. Using a stable cell line expressing psychLight, we correctly predicted the hallucinogenic behavioral effects of compounds even with structural similarity and with previously unknown hallucinogenic potentials. We further used psychLight to identify a novel, non-hallucinogenic psychedelic analog, which promoted structural neural plasticity and produced rapid- and long-lasting antidepressant-like effects after a single administration. The advent of psychLight will enable early identification of abusive designer drugs and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.