Structure-based discovery of nonhallucinogenic psychedelic analogs

This neurochemistry 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 hallucinogenic 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-HT_2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT_2AR 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-HT_2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT_2AR 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.”

Authors: Dongmei Cao, Jing Yu, Huan Wang, Zhipu Luo, Xinyu Liu, Licong He, Jianzhong Qi, Luyu Fan, Lingjie Tang, Zhangcheng Chen, Jingsong Li, Jianjun Cheng & Sheng Wang

Notes

“Psychedelic drugs such as lysergic acid diethylamide (LSD) and mushroom-derived psilocybin exert their effects by binding the serotonin 2A receptor (5-HT2AR). These drugs also have antidepressant effects, but the hallucinations they cause complicate their use as therapeutics. Cao et al. present structures of 5-HT2AR bound to psychedelic drugs, the endogenous ligand serotonin, and the non-hallucinogenic drug lisuride. The structures reveal ligand-receptor interactions that cause a bias toward arrestin recruitment. Based on these insights, the authors designed arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. Arrestin recruitment alone is insufficient for antidepressant effects, but the low G-protein signalling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination. —VV”