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Scientists Have Developed a New Antidepressant Molecule

Psilocybin is a natural hallucinogen extracted from poisonous mushrooms, multiple studies have confirmed its potential to treat depression, and in 2019, it was recognized by the U.S. Food and Drug Administration as a breakthrough therapy for major depressive disorder and drug-resistant depression, however, how to separate the antidepressant effect from the hallucinogenic effect remains difficult. Our scientists have developed a new class of antidepressant molecules without hallucinogenic effects based on the mechanism of action between hallucinogens and receptors. The study was published in the journal Science under the title”Structure-based discovery of nonhallucinogenic psychedelic analogs”
The hallucinogens known so far all produce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). This study found that when serotonin, the endogenous ligand, and dephosphorylated psilocybin, a metabolite of psilocybin, respectively, bind to 5-HT2AR, there is another new binding mode regulated by the lipid molecule monooleate, leading to a biased activation of downstream β-arrestin signaling. The researchers further synthesized β-arrestin signal-preferred compounds based on the structure, and screened out the compound IHCH-7086. The mouse experiments found that IHCH-7086 can significantly improve the depressive-like behavior of mice, and did not show hallucinogenic effects.
This study not only revealed the molecular mechanism of hallucinations, but also found a new class of molecules that are expected to treat depression, providing a new idea for the development of fast-acting and long-acting antidepressant drugs.
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