Drug treatments for depression, anxiety, and alcohol addiction are showing promise despite being illegal for recreational use. Hallucinations and profound emotional experiences are believed to lead to long- lasting therapeutic effects. The therapeutic effects might remain if the "trip" could be eliminated. The researchers at UNC-Chapel Hill, UC San Francisco, Yale, Duke, and Stanford have taken a big step towards answering that question.
The research published in Nature shows that it is possible to create a compound that hits the same target as a drug, but does not cause the same effects on mice. The new compound triggered the same anti-depressant action that researchers have observed in mice treated with SSRI drugs over the past two decades with just two differences: the anti-depressant action of the new compound was immediate and long- lasting after just one dose.
"We were very surprised the compound had any anti-depressant activity similar to ketamine and psilocybin, both rapidly acting antidepressants," said co- senior author Bryan L. We ran a chemistry experiment to see if we could make a compound that would work with 5-HT2A. We decided to conduct experiments in mice once we accomplished that.
The compound is patented by Yale, UNC-Chapel Hill, and UCSF and licensed to Onsero, a company created to fine- tune experimental compounds before they can be further tested.
We don't know if the same effects will be seen in people. We would like to find out. It would be a game-changing therapy to help people with treatment- resistant depression.
There is a case for the drug.
The active ingredient in magic mushrooms, pscilocin, is bound to the 5-HT2A serotonin receptors on the surface of the brain. The cascade of chemical signals inside cells can be triggered by thereceptor. The person was sent on a hallucinogenic trip by the communication between these cells and other cells. The effect of the drugs can last for many months for people who are treatment resistant.
Severe depression has become a factor in the use of ketamine. The FDA approved a prescription version of the drug esketamine. It is expensive to use this drug and it requires supervision. Anti-depressant effects are shown in a brew that includes two plants. One of its active ingredients, N, N-Dimethyltryptamine, is illegal in the United States.
It would be hard to scale up these drugs to help the millions of people in need as they can change brain chemistry and carry risks. Despite coming out the other side feeling better, an individual's experience can still be frightening.
Serotonin signaling is not the same as it is in the case of psychedelic drugs. One reason why the drugs can cause a wide swath of unpleasant side effects is that they increase the levels of a brain chemical. People who take the drugs don't usually feel the anti-depressant until weeks later.
"So, there's more going on than just raising serotonin levels to treat depression, and that's what I found when I spent two decades seeing psychiatric patients." Changes in the brain caused bySSRIs leads to anti-depressive action. We're not sure what's going on. I know a lot of people who have had their lives changed by therapy.
The idea is simple: if scientists could create a compound that hits the 5-HT2A receptor but doesn't cause any side effects, they would be able to treat depression without the side effects associated with other drugs.
It took seven years for the project to be completed, starting with the discovery of the chemical structure of the Serotonin Receptor. It took a long time.
In 2020, the Defense Advanced Research Projects Agency (DARPA) in the Department of Defense funded the creation of new medications that treat depression, anxiety, and substance abuse without major side effects. The UNC lab's expertise, experience, and collaborations with experts in the field secured this high-risk, high-reward project.
The years of science collaborating.
Jonathan Ellman, a professor of chemistry at Yale, and Danielle Confair, a senior scientist at AstraZeneca, led the development of a sequence of reactions. The basic building blocks of many compounds, including medications, are the result of chemical reactions for the synthesis of THPs, which occur in nature.
Computational simulations were used to home in on specific THP-based virtual compounds most likely to only bind to 5-HT2A.
The project began as an opportunity to expand the new virtual libraries with 75 million tricked-out molecule from the Ellman lab. When we started to see the unusual signaling from the new compounds and their amazing permeability into the brain, we started to think these compounds might have interesting effects.
The UNC lab, led by co-first author Kuglae Kim, selected and tested several actual compounds to see how they bind to the dopaminergic system in the brain. This part took a long time as well. There are a lot of perfectly situated proteins. X-ray crystallography is one of the methods used to observe a compound's effect.
Each experiment yielded more information about the compound's relationship to 5-HT2A. Shoichet's team used that knowledge to modify their chemical design in order to create a virtual compound.
This iterative process yielded a few compounds that could be tested in a mouse model to see if they bind to 5-HT2A.
What we saw was completely unforeseen. It had the same anti-depressant drug action as does ketamine but not the same hallucinogenic drug action.
Drug action in mice can be studied to see if the mice were depressed or hallucinating. Standard tests have been used for decades when testing suppressed compounds. Mouse models of drug action have been used by researchers over the years. Humans and mice behave in similar ways when given hallucinogenic drugs.
The research team observed the same anti-depressant drug action when they gave mice the new compound.
It was remarkable to us that this compound was effective in all mouse models after a single dose, and the effect was long lasting. We were fortunate. We know we aren't done.
It's not yet known whether this drug or others like it can provide a one-dose, long- lasting anti-depressant effect for people with treatment-resistant depression. This research shows that it's possible.
More information: Brian Shoichet, Bespoke library docking for 5-HT2A receptor agonists with anti-depressant activity, Nature (2022). DOI: 10.1038/s41586-022-05258-z Journal information: Nature
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