Researchers at UC Davis have developed a light driven technique that converts amino acids, the molecules that make up proteins, into compounds that behave similarly 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 disorder. Unlike traditional psychedelics, however, the compounds did not produce key hallucinogenic-like behaviors in animal testing.
The findings were published in the Journal of the American Chemical Society.
"The question that we were trying to answer was, 'Is there whole new class of drugs in this field that hasn't been discovered?" said study author Joseph Beckett, a Ph.D. student working with Professor Mark Mascal, UC Davis Department of Chemistry, and an affiliate of the UC Davis Institute for Psychedelics and Neurotherapeutics (IPN). "The answer in the end was, 'Yes.'"
The work could lead to a more efficient and environmentally friendly approach for discovering serotonin-targeting drugs that provide some of the therapeutic effects linked to psychedelics without dramatically altering perception.
"In medicinal chemistry, it's very typical to take an existing scaffold and make modifications that just tweak the pharmacology a little bit one way or another," said study author Trey Brasher, also a Ph.D. student in the Mascal Lab and an affiliate of IPN. "But especially in the psychedelic field, completely new scaffolds are incredibly rare. And this is the discovery of a brand-new therapeutic scaffold."
Building New Psychedelic-Like Molecules With UV Light
To create the compounds, the researchers combined several amino acids with tryptamine, a naturally occurring metabolite derived from the essential amino acid tryptophan. The team then exposed the resulting molecules to ultraviolet light, triggering chemical changes that produced entirely new compounds with potential medical applications.
Using computer modeling, the scientists evaluated how strongly 100 of the new compounds interacted with the brain's 5-HT2A serotonin receptor.
From that group, five compounds were selected for more detailed laboratory testing. Their activity levels ranged from 61% to 93%. The strongest performer acted as a full agonist, meaning it could trigger the maximum biological response possible from the 5-HT2A receptor system.
Researchers named this compound D5.
A Surprising Result in Mouse Experiments
Because D5 fully activated the same receptor targeted by psychedelics, the scientists expected it to produce head twitch responses in mice, a widely used indicator of hallucinogenic-like effects.
That did not happen.
Even though D5 strongly activated the receptor, the mice did not display the expected psychedelic-like behavior.
"Laboratory and computational studies showed that these molecules can partially or fully activate serotonin signaling pathways linked to both brain plasticity and hallucinations, while experiments in mice demonstrated suppression of psychedelic-like responses rather than their induction," Beckett and Brasher said.
Why Didn't the Compound Cause Hallucinations?
The research team now plans to investigate whether other serotonin receptors may be reducing or blocking the hallucinogenic-like effects produced by D5.
"We determined that the scaffold itself possesses a range of activity," Brasher said. "But now it's about elucidating that activity and understanding why D5 and similar molecules are non-hallucinogenic when they're full agonists."
Additional authors on the paper include Mark Mascal and Lena E. H. Svanholm, of UC Davis; Marc Bazin, Ryan Buzdygon and Steve Nguyen, of HepatoChem Inc.; John D. McCorvy, Allison A. Clark and Serena S. Schalk, of the Medical College of Wisconsin; and Adam L. Halberstadt and Bruna Cuccurazza, of UC San Diego.
The research reported on here was funded by grants from the National Institutes of Health and Source Research Foundation.
