Structure-based discovery of nonhallucinogenic psychedelic analogs
Cao, D., Chen, Z., Cheng, J., He, L., Liu, X., Luo, Z., Qi, J., Tang, L., Wang, H., Wang, S., Yu, J.
This cell and mice study (2022) presents structures of the serotonin receptor 5-HT2RA bound to psilocin, LSD, serotonin and the non-hallucinogenic analogue lisuride. The researchers were then able to design arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. The research presented here provides a foundation for the design of safe and effective non-hallucinogenic psychedelic analogues.
Abstract
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and D-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the non-hallucinogenic psychedelic analogue lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic analogues with therapeutic effects.