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A light-triggered chemistry approach is giving researchers a way to “remix” simple biological building blocks into entirely new brain-active shapes. Credit: Shutterstock
Scientists at UC Davis created a new class of serotonin-targeting molecules using a light-driven chemical method.
UC Davis scientists have created a light-based technique that converts amino acids — the building blocks of proteins — into new molecules with psychedelic-like shapes and brain activity.
These compounds can switch on the brain’s serotonin 5-HT2A receptors, which are linked to cortical neuron growth, making them potential leads for conditions such as depression, substance-use disorder and PTSD. In animal models, though, the molecules did not produce a key behavioral sign typically associated with hallucinogenic drugs.
The research was recently 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 findings point to a simpler, more environmentally friendly path for discovering serotonin-targeting medicines that may deliver psychedelic-like benefits without strongly 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.”
Discovering a new therapeutic scaffoldTo build their collection of candidate molecules, the team paired different amino acids with tryptamine, a metabolite of the essential amino acid tryptophan. Next, they exposed these combined molecules to ultraviolet light, reshaping them into new compounds with potential medicinal usefulness.
Computer simulations were used to test the binding affinity of 100 of these compounds at the 5-HT2A receptor.
From that set, five compounds were chosen for additional laboratory tests of efficacy and potency. The selected candidates showed efficacies ranging from 61% to 93%, with 93% indicating a full agonist — a compound capable of producing the maximum biological response from the 5-HT2A system.
The team labeled the full agonist in the group as D5. They expected that administering the compound to mouse models would induce head twitch responses, a hallmark of hallucinogenic-like behaviors.
However, that wasn’t the case. Despite fully activating the same receptor as psychedelics, D5 didn’t induce head twitch responses.
“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.
Next steps: why no hallucinations?The team plans to conduct follow-up studies to better understand if other serotonin receptors in the brain modulate or suppress the hallucinogenic-like effects of 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.”
Reference: “Transforming Amino Acids into Serotonin 5-HT2A Receptor Ligands Using Photochemistry” by Joseph O. S. Beckett, Ryan Buzdygon, Steven Nguyen, Allison A. Clark, Serena S. Schalk, Lena E. H. Svanholm, Trey J. Brasher, Marc Bazin, Bruna Cuccurazzu, Adam L. Halberstadt, John D. McCorvy and Mark Mascal, 16 December 2025, Journal of the American Chemical Society.
DOI: 10.1021/jacs.5c19817
Funding: National Institute of Mental Health, National Institutes of Health, Source Research Foundation
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