A group of scientists have reported findings that provide a foundation for the structure-based design of safe and effective non-hallucinogenic, rapid-acting antidepressants.
Psychedelic medicines are showing promising results for a number of indications such as depression, anxiety and PTSD. However, many drug development companies are searching for psychedelic compounds without the trip – as this aspect can make it difficult to deliver care at scale.
A team of scientists have now reported for the first time a structure-based strategy to design novel rapid-acting antidepressant compounds.
The team was led by Dr Wang Sheng at the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, and Dr Cheng Jianjun at the iHuman Institute, ShanghaiTech University.
The findings have been published in the journal Science.
Extended binding pocket binding
Psilocybin – the psychedelic compound found in a number of different mushrooms – is converted in the liver to pharmacologically active psilocin, which then acts on serotonin 2A receptors (5-HT2AR) in the brain.
For the study, the team produced six new crystal structures of 5-HT2AR that bound to compounds including psilocin, LSD, serotonin and non-hallucinogenic psychedelic analogues.
The team discovered that psilocin displayed an unexpected binding mode known as the “extended binding pocket” (EBP) mode, which is regulated by lipids. They also found that compounds that occupied more EBP than “orthosteric binding pocket” (OBP) – the usual site for receptor binding – were associated with anti-depressive activity in test animals without triggering hallucinations.
The scientists then designed several new psychedelic analogues they thought would favour EBP binding over OBP binding.
After repeating behavioural tests on mice receiving the compounds, the team found that two compounds – IHCH-7079 and IHCH-7806 – did not trigger “head twitch behaviour”, which is commonly seen as indicative of hallucinations.
Instead, the mice displayed standard behavioural measures, which the authors suggest means that the compounds were effective antidepressants.
Science explains that: “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 signaling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination.”
The authors state: “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.”
The team pointed out that the compounds reported in the study are not approved drugs, and further preclinical and clinical studies are needed to verify their safety and antidepressant effects in humans.
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