A scientific first: How psychedelics bind to key brain cell receptor


Date:
September 17, 2020
Source:
University of North Carolina Health Care
Summary:
For the first time, scientists solved the high-resolution structure
of these compounds when they are actively bound to the 5-HT2A
serotonin receptor on the surface of brain cells. This discovery is
already leading to the exploration of more precise compounds that
could eliminate hallucinations but still have strong therapeutic
effects. Psilocybin - the psychedelic compound in mushrooms -
has already been granted breakthrough status by the FDA to treat
depression.



FULL STORY ========================================================================== Psychedelic drugs such as LSD, psilocybin, and mescaline cause severe
and often long-lasting hallucinations, but they show great potential
in treating serious psychiatric conditions, such as major depressive
disorder. To fully investigate this potential, scientists need to know
how these drugs interact with brain cells at the molecular level to
cause their dramatic biological effects.

Scientists at UNC-Chapel Hill and Stanford have just taken a big step
in that direction.


==========================================================================
For the first time, scientists in the UNC lab of Bryan L. Roth,
MD, PhD, and the Stanford lab of Georgios Skiniotis, PhD, solved the high-resolution structure of these compounds when they are actively bound
to the 5-HT2A serotonin receptor (HTR2A) on the surface of brain cells.

This discovery, published in Cell, is already leading to the exploration
of more precise compounds that could eliminate hallucinations but still
have strong therapeutic effects. Also, scientists could effectively
alter the chemical composition of drugs such as LSD and psilocybin --
the psychedelic compound in mushrooms that has been granted breakthrough
status by the FDA to treat depression.

"Millions of people have taken these drugs recreationally, and now they
are emerging as therapeutic agents," said co-senior author Bryan L. Roth,
MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at
the University of North Carolina School of Medicine. "Gaining this first glimpse of how they act at the molecular level is really important,
a key to understanding how they work. Given the remarkable efficacy of psilocybin for depression (in Phase II trials), we are confident our
findings will accelerate the discovery of fast- acting antidepressants
and potentially new drugs to treat other conditions, such as severe
anxiety and substance use disorder." Scientists believe that activation
of HTR2A, which is expressed at very high levels in the human cerebral
cortex, is key to the effects of hallucinogenic drugs. "When activated,
the receptors cause neurons to fire in an asynchronous and disorganized fashion, putting noise into the brain's system," said Roth, who holds
a joint faculty appointment at the UNC Eshelman School of Pharmacy.

"We think this is the reason these drugs cause a psychedelic
experience. But it isn't at all clear how these drugs exert their
therapeutic actions." In the current study, Roth's lab collaborated with Skiniotis, a structural biologist at the Stanford University School of Medicine. "A combination of several different advances allowed us to do
this research," Skiniotis said.

"One of these is better, more homogeneous preparations of the receptor proteins. Another is the evolution of cryo-electron microscopy technology, which allows us to view very large complexes without having to crystalize them." Roth credits co-first author Kuglae Kim, PhD, a postdoctoral
fellow in his lab, for steadfastly exploring various experimental methods
to purify and stabilize the very delicate serotonin receptors.



========================================================================== "Kuglae was amazing," Roth said. "I'm not exaggerating when I say what
he accomplished is among the most difficult things to do. Over three
years in a deliberate, iterative, creative process, he was able to
modify the serotonin protein slightly so that we could get sufficient quantities of a stable protein to study." The research team used Kim's
work to reveal the first X-ray crystallography structure of LSD bound to
HTR2A. Importantly, Stanford investigators then used cryo-EM to uncover
images of a prototypical hallucinogen, called 25-CN-NBOH, bound together
with the entire receptor complex, including the effector protein Gaq. In
the brain, this complex controls the release of neurotransmitters and influences many biological and neurological processes.

The cryo-EM image is like a map of the complex, which Kim used to
illustrate the exact structure of HTR2A at the level of amino acids --
the basic building blocks of proteins such as serotonin receptors.

Roth, a psychiatrist and biochemist, leads the Psychoactive Drug Screening Program, funded by the National Institute of Mental Health. This gives
his lab access to hallucinogenic drugs for research purposes. Normally,
these compounds are difficult to study in the lab because they are
regulated by the Drug Enforcement Agency as Schedule 1 drugs.

Roth and colleagues are now applying their findings to structure-based
drug discovery for new therapeutics. One of the goals is to discover
potential candidates that may be able offer therapeutic benefit without
the psychedelic effects.

"The more we understand about how these drugs bind to the receptors,
the better we'll understand their signaling properties," Skiniotis
says. "This work doesn't give us the whole picture yet, but it's a fairly
large piece of the puzzle."

========================================================================== Story Source: Materials provided by
University_of_North_Carolina_Health_Care. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Kuglae Kim, Tao Che, Ouliana Panova, Jeffrey F. DiBerto, Jiankun
Lyu,
Brian E. Krumm, Daniel Wacker, Michael J. Robertson, Alpay B. Seven,
David E. Nichols, Brian K. Shoichet, Georgios Skiniotis, Bryan
L. Roth.

Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin
Receptor. Cell, 2020; 182 (6): 1574 DOI: 10.1016/j.cell.2020.08.024 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200917181259.htm

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