Structure-based discovery of nonhallucinogenic psychedelic analogs
Science – January 27, 2022
Source: OpenAlex
Summary
A breakthrough in pharmacology reveals a path to safer therapies, creating non-hallucinogenic compounds with antidepressant potential. By mapping how Lysergic acid diethylamide (LSD) and psilocin, a psilocybin metabolite, interact with the brain's 5-HT receptor, neuroscience advances. Crucially, serotonin and psilocin exhibit a unique second binding mode. This chemical understanding, vital for drug studies and chemical synthesis, allowed the design of new psychedelics. These compounds, influencing neurotransmitter receptor behavior, showed antidepressant-like activity in mice without hallucinogenic effects, promising targeted treatments for the serotonin receptor.
Abstract
Drugs that target the human serotonin 2A receptor (5-HT 2A R) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT 2A R 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 nonhallucinogenic psychedelic analog 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 2A R β-arrestin–biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT 2A R complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.