Cell: For the first time, a three-dimensional structure of hallucinogens combined with 5-HT2A serotonin ligands has been analyzed.

September 23, 2020 /--- Hallucinogens such as lSD, psilocybin and mescaline can cause severe and often persistent hallucinations, but they show great potential in treating serious mental illnesses such as severe depression.
to fully study this potential, scientists need to know how these drugs interact with brain cells at the molecular level to cause their dramatic biological effects.
a new study, Dr. Bryan L. Roth of the University of North Carolina at Chapel Hill and Dr. Georgios Skiniotis of Stanford University and their colleagues took a big step in that direction.
they first analyzed the high-resolution structure of these hallucinogens when combined with 5-HT2A serotonin receptors (5-HT2A serotonin receptors, HTR2A) on the surface of brain cells.
study was published in the September 17, 2020 issue of cell, under the title "Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor."
from Cell, 2020, doi:10.1016/j.cell.2020.08.024.
findings have led to the exploration of more precise compounds that can eliminate hallucinations, but still have strong therapeutic effects.
In addition, scientists can effectively alter the chemical composition of drugs such as LSD and naked-cap mushrooms, hallucinogenic compounds found in mushrooms, which have been given a breakthrough by the U.S. Food and Drug Administration (FDA) to treat depression.
"Millions of people are taking these drugs for recreation, and now they're becoming therapeutic drugs," said Dr. Bryan L. Roth, co-author of the paper and a professor of pharmacology at the University of North Carolina at Chapel Hill School of Medicine.
it's really important to understand for the first time how they work at the molecular level, and that's the key to understanding how they work.
West given the remarkable efficacy of naked mushrooms for depression (in Phase II clinical trials), we believe our findings will accelerate the discovery of fast-acting antidepressants and potentially lead to the discovery of new drugs to treat other diseases such as severe anxiety and substance use disorders."
" scientists believe that HTR2A has a very high level of expression in the human cerebral cortical layer, and its activation is key to the functioning of hallucinogenic drugs.
, when activated, the subject causes neurons to discharge out of step and out of order, allowing noise to be entered into the brain system," Roth said.
we think these drugs cause psychedelic experiences.
it is not clear how these drugs play their therapeutic role.
new study, Roth Labs collaborated with Skiniotis, a structural biologist at Stanford University School of Medicine.
s combination of several different research advances allowed us to conduct this study," said Skiniotis, a researcher at the University of New China.
one of these is to prepare a better, more uniform 5-HT2A protein.
is cryo-EM, which allows us to observe very large compounds without having to crystallize them.
" Roth praised Dr. Kuglae Kim, a postdoctoral researcher at his lab, for his unwavering exploration of experimental methods to purify and stabilize the very fragile serotonin-infested HTR2A.
, "Kim is amazing," Roth said.
no exaggeration to say that the work he did was one of the hardest things to do.
three years, in a deliberate, repetitive, creative process, he was able to modify the serotonin protein slightly so that we could get enough stable proteins to study it.
" Roth team used Kim's research to reveal for the first time the X-ray crystal structure when LSD is combined with HTR2A.
importantly, Skiniotis and his team then used cryogenic electroscope technology to reveal images of a prototype hallucinogen called 25-CN-NBOH that binds to the entire subject complex, including the effect protein G alphaq.
in the brain, the complex controls the release of neurotransmitters and affects many biological and neural processes.
Kim uses cryogenic electroscopic images to illustrate the precise structure of HTR2A at amino acid levels.
Roth and colleagues are now applying their findings to new structure-based drug discoveries in order to develop new therapeutic drugs.
one of the goals is to identify potential drug candidates who may be able to provide therapeutic benefits without hallucinogenic effects.
the more we know about how these drugs bind to HTR2A subjects, the better we understand their signal transductivity properties," said Skiniotis.
study has not provided us with a full picture, but it provides a significant portion of it.
" (bioon.com) Reference: 1.Kuglae Kim et al. Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 2020, doi:10.1016/j.cell.2020.08.024.2.A scientific first: How psychedelics bind to key brain cell receptor.