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Synthetic Psychedelic Compounds May Treat Depression Without the Trip, Study Suggests

By Alexander Beadle

Published: Oct 10, 2022   
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Scientists have developed a new compound which interacts with the same therapeutic targets in the brain as psychedelic drugs, producing the same long-lasting antidepressant and antianxiety effects but without the psychedelic high.

Published in Nature, the study used a computational library of around 75 million candidate molecules. The researchers assessed which of these molecules fitted well against a model of the 5HT2a brain receptor, which is the main target of psychedelics.

The best-fit candidate compound was then synthesized and given to laboratory mice. Following a series of behavioral tests, the researchers concluded that a single dose of the new compound could be used as an effective and long-lasting antidepressant.

Whether this new drug can provide a similar benefit in humans is yet to be determined, but the researchers believe these results indicate that it may be possible.

Screening molecular libraries returned surprising new results

This research is the culmination of around half a dozen years of work by a team of researchers from UC San Francisco, UNC-Chapel Hill and Yale University, which later expanded to also include Duke and Stanford universities.

Initially, the team did not even set out to look for novel antidepressants. The research was intended to be an opportunity to screen a new virtual library of tetrahydropyridine-type compounds, which have generally been absent from larger molecular libraries in the past. But, as the researchers explain in their paper, this structural motif is already commonly seen among many FDA-approved drugs.

“For us, the project began as an opportunity to expand the new virtual libraries with 75 million tricked-out molecules from the Ellman lab,” Brian Shoichet, professor of pharmaceutical chemistry in the UCSF School of Pharmacy, told the UNC Chapel Hill Newsroom. Jonathan Ellman, a professor of pharmacology at Yale, was also responsible for synthesizing the eventual candidate compounds.

“It was only when we started to see the unusual signaling from the new compounds and their amazing permeability into the brain that we as a team started to think these compounds might have interesting effects in vivo.”

To evaluate such effects, the team needed a good model of the 5HT2a receptor to work with. Bryan Roth, a professor of pharmacology at the UNC School of Medicine and director of the NIMH Psychoactive Drug Screening Program, and his colleagues had recently solved the crystal structure of the 5TH2b receptor, and so his group began to work on doing the same for 5HT2a.

“There wasn’t really any sense that drugs like psychedelics that activate this receptor would be therapeutic until psilocybin was tried in clinical trials for depression and shown to have this remarkable effect,” said Roth in a press release. “That really galvanized our interest, which basically started this collaboration.”

LSD-like compound shows antidepressant effect in mice, but no high

Using computational calculations, the multi-institutional research group was able to model the interactions between each molecule in this new library and the 5HT2a serotonin receptor model.

Each of the 75 million compounds in this library was assessed for an average of 92 unique conformations and 23,000 spatial orientations. The top 4,000 best-performing compounds were then manually inspected for any unfavorable features that may not have been detected by the computational docking calculations.

After screening, optimizing, and re-screening, the team settled on 17 candidate tetrahydropyridine compounds that warranted chemical synthesis.

Each of these compounds was then subject to testing by radioligand displacement assay, with four compounds showing significant agonist or antagonist behavior at the 5HT2a, 5HT2b and 5HT2c receptor subtypes.

“We were very surprised the compound had any anti-depressant activity similar to ketamine and psilocybin, both rapidly acting antidepressant psychedelic drugs,” said Roth. “We were basically running a chemistry experiment to see if we could create a compound to activate 5-HT2A. Once we achieved that, we decided to run experiments in mice.”

LSD-like compound shows antidepressant effect in mice, but no high

To examine whether these new compounds might have any interesting effects in vivo, the researchers studied the behavior of lab mice given one of the two best-performing new compounds, a vehicle placebo, or a psychedelic compound such as psilocin.

Depressive effects were evaluated using a standard forced swim test and tail suspension tests, as well as a novel suppressed feeding test. Based on the behavior of the mice, the researchers concluded that the new compounds did have similar long-lasting anti-depressive effects to psychedelics.

But notably, the mice given the new tetrahydropyridine compounds did not exhibit the same kind of rapid head twitch behavior seen in the mice given psychedelics. This head twitch has commonly been used as an indicator for a psychedelic trip.

“What we saw was completely unexpected,” Roth said. “Not only did the compound bind the 5-HT2A serotonin receptor like we thought it would, but it had the same antidepressant drug action as does ketamine but not the same hallucinogenic drug action.”

“The final molecules were 100 times more potent than what we started with,” Shoichet added, although he noted that while the candidate compounds were stronger than traditional antidepressants, they were still not nearly as strong as LSD. “In the animals they are very potent, much more potent than Prozac.”

Firstly, the researchers say that this study demonstrates the value of exploring under-represented or bespoke virtual molecule libraries for specific pharmacological applications. More specifically, they are hopeful that the molecules discovered in this analysis could become potential leads in the development of novel antidepressants.

“We don’t know if we’ll see the same effects in people,” Roth said. “But we hope to find out. It would be a game changer to create a one-dose, long-acting therapy to help people with treatment-resistant depression and other conditions.”


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