Researchers at the University of California, Davis have developed a light-driven technology that converts amino acids, the building blocks of proteins, into compounds that behave similar to psychedelics in the brain. These newly created molecules activate serotonin 5-HT2A receptors, which are associated with brain cell growth, and are considered promising targets for treating conditions such as depression, PTSD, and substance use disorders. However, unlike traditional hallucinogens, this compound did not cause significant hallucinogen-like behavior in animal studies.
The survey results are Journal of the American Chemical Society.
“The question we were trying to answer was, ‘Are there entirely new classes of drugs in this field that haven’t been discovered yet?'” says study author Dr. Joseph Beckett. students working with Professor Mark Maskull of the UC Davis Department of Chemistry and affiliates of the UC Davis Institute for Psychedelic and Neurotherapeutics (IPN). “The final answer was ‘yes’.”
This research could lead to a more efficient and environmentally friendly approach to discovering serotonin-targeting drugs that provide some of the therapeutic effects associated with psychedelics without dramatically altering perception.
“It’s very common in medicinal chemistry to take an existing scaffold and make changes that just slightly tweak the pharmacology in some way,” said study author Trey Brasher, a Ph.D. student at Mascal Lab and affiliated with IPN. “But completely new scaffolds are incredibly rare, especially in the psychedelic field. And this is the discovery of an entirely new therapeutic scaffold.”
Building new psychedelic molecules with UV light
To create this compound, researchers combined several amino acids with tryptamine, a natural metabolite derived from the essential amino acid tryptophan. The team then exposed the resulting molecules to ultraviolet light to cause chemical changes that produced entirely new compounds with potential medical applications.
Scientists used computer modeling to assess how strongly 100 new compounds interacted with the brain’s 5-HT2A serotonin receptors.
From that group, five compounds were selected for more detailed clinical testing. Their activity levels ranged from 61% to 93%. Those with the strongest performance acted as full agonists. This means that it can elicit the maximum possible biological response from the 5-HT2A receptor system.
The researchers named this compound D5.
Surprising results in mouse experiments
Because D5 fully activates the same receptors that hallucinogens target, the scientists expected that D5 would trigger a head-twitch response in mice, which is widely used as an indicator of hallucinogen-like effects.
That didn’t happen.
Despite D5 strongly activating the receptor, the mice did not exhibit the expected psychedelic behavior.
“Laboratory and computational studies have shown that these molecules can partially or fully activate the serotonin signaling pathway, which is associated with both brain plasticity and hallucinations, while experiments in mice demonstrated inhibition rather than induction of psychedelic-like responses,” Beckett and Brasher said.
Why didn’t the compound cause hallucinations?
The research team now plans to investigate whether other serotonin receptors reduce or block the hallucinogenic effects produced by D5.
“We determined that the scaffolding itself has a variety of activities,” Brasher said. “But now it is important to elucidate its activity and understand why D5 and similar molecules are not psychedelic despite being full agonists.”
Additional authors on the paper include Mark Mascal and Lena EH Svanholm of the University of California, Davis. Marc Bazin, Ryan Buzdygon, and Steve Nguyen of HepatoChem Inc.; John D. McCorvey, Alison A. Clark, and Selina S. Schalk of the Medical College of Wisconsin; Adam L. Halberstadt and Bruna Cuclazza of the University of California, San Diego;
The research reported here was funded by grants from the National Institutes of Health and the Source Research Foundation.
