Scientists investigate how psychedelic drugs interact with brain cells at the molecular level

Reviewed by Emily Henderson, B.Sc.September 18, 2020

Psychedelic drugs such as LSD, psilocybin, and mescaline cause severe, often long-lasting hallucinations, but offer great potential for the treatment of serious mental conditions such as major depressive disorder.

To fully investigate this possibility, scientists need to know how these drugs interact with brain cells at the molecular level, causing dramatic biological effects. Scientists at UNC Chapel Hill and Stanford have taken a major step in that direction.

UNC Labs by Dr. Brian L. Ross (Doctor of Medicine, Ph.D.) and scientists by Dr. Georgios Skiniotis (Stanford Institute) have solved the high-resolution structure of these compounds for the first time. Actively Bind to 5-HT_2A Serotonin receptors (HTR2A) on the surface of brain cells.

This discovery cellAlready leads to the search for more accurate compounds that can eliminate hallucinations but still have powerful therapeutic effects. Scientists can also effectively change the chemical composition of drugs such as LSD and psilocybin, a psychedelic compound of mushrooms that has been given a breakthrough status by the FDA for the treatment of depression.

Brian L. Ross, MD, co-chief author of Professor Michael Hooker’s Pharmacology at the University of North Carolina School of Medicine, said: ..

“This first glimpse of how they work at the molecular level is very important as the key to understanding how they work. Effectiveness of In the depressive psilocybin (Phase II trial), this discovery could accelerate the discovery of fast-acting antidepressants and become a new drug to treat other conditions such as severe anxiety and substance abuse. I’m sure. “

Scientists believe that activation of HTR2A, which is expressed at very high levels in the human cerebral cortex, is key to the effectiveness of hallucinogens.

“When receptors are activated, neurons fire in an asynchronous and chaotic manner, causing noise in the brain system,” said Ross, a co-teacher at the UNC Eshelman School of Pharmacy. It was. “I think this is why these drugs cause a psychedelic experience, but it’s not entirely clear how these drugs work.”

In the current study, Ross’s lab collaborated with Skiniotis, a structural biologist at Stanford Medical School.

“The combination of several different advances has allowed us to do this work,” Skiniotis said. “One of these is a better, more uniform preparation of receptor proteins. The other is the evolution of cryo-electron microscopy technology that allows us to observe very large complexes without crystallization.”

Roth acknowledges co-author Dr. Kuglae Kim, a postdoctoral fellow in the lab, who is steadily exploring a variety of methods for purifying and stabilizing highly delicate serotonin receptors.

“Kugura was great,” Ross said. “It’s no exaggeration to say that what he achieved is one of the most difficult things to do. For three years, in a deliberate and repetitive creative process, he changed the serotonin protein slightly enough. A stable protein for studying large amounts. “

The research team used Kim’s work to reveal the first X-ray crystal structure of LSD bound to HTR2A. Importantly, researchers at Stanford University used cryo-EM to reveal images of a prototype hallucinogen called 25-CN-NBOH that bound to the entire receptor complex containing the effector protein Gαq. In the brain, this complex controls the release of neurotransmitters and affects many biological and neurological processes.

Cold EM images are like a map of the complex that Kim used to explain the exact structure of HTR2A at the level of amino acids, which are the basic building blocks of proteins such as serotonin receptors.

Ross, a psychiatrist and biochemist, leads a psychoactive drug screening program funded by the National Institute of Mental Health. This gives the laboratory access to hallucinogens for research purposes. These compounds are regulated by the Drug Enforcement Administration as Schedule 1 drugs and are usually difficult to study in the laboratory.

Roth and his colleagues are now applying the findings to structure-based drug discovery in search of new therapies. One of the goals is to find candidates who have the potential to provide therapeutic effects without psychedelic effects.

The more we understand how these drugs bind to their receptors, the better we can understand their signaling properties. I don’t know the whole picture yet in this work, but it’s a fairly large puzzle piece. “

Georgios Skiniotis, Ph.D., Stanford Medical School, Structural Biologist