Analogs of drugs like psilocybin and LSD show antidepressant-like activity in mice without causing hallucination, researchers report. The findings may provide a foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic therapeutic drugs. Serotonin is a neurotransmitter that modulates most human behavioral processes. Drugs that target serotonin receptors, particularly the human serotonin 2A receptor (5-HT2aR), are widely used to treat neuropsychiatric diseases. However, many of these drugs are known to have hallucinogenic effects. Previous research has shown that the serotonergic hallucinogens – psychedelics including LSD and psilocybin, which bind to 5-HT2aR – have promising potential as rapid and enduring therapeutics for treating PTSD, anxiety and depression. Despite this, the characteristic hallucinations these compounds cause can hamper their use. According to the authors, non-hallucinogenic psychedelic analogs could offer an alternative solution, but it remains unclear how to rationally design such compounds and whether the hallucinogenic effects of psychedelics are necessary for therapeutic effects. Here, Dongmei Cao and colleagues describe several crystal structures of 5-HT2aR bound to the psychedelic drugs LSD and psilocin, endogenous serotonin and a non-hallucinogenic psychedelic lisuride. They reveal a second binding mode for serotonin and psilocin. Using this new information, Cao et al. used a structure-based approach to design the novel psychedelic IHCH-7113 as well as several 5-HT2aR β-arrestin-biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. “[W]e anticipate that the reported structures herein will accelerate the search for new psychedelics and nonhallucinogenic psychedelic analogs for treatment of neuropsychiatric diseases,” write the authors.
Structure-based discovery of non-hallucinogenic psychedelic analogs
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