Researchers Discover New Therapeutic Scaffold Targeting 5-HT2A Receptors

Researchers at the University of California, Davis, led by Professor Mark Mascal in collaboration with colleagues at the UC Davis Institute for Psychedelics and Neurotherapeutics, have developed a light-activated chemical method that converts simple amino acids into new brain-active molecules. The compounds activate the serotonin 5-HT2A receptor, a key target of psychedelic drugs, yet did not produce hallucinogenic-like behavior in animal models. The study appears in the Journal of the American Chemical Society and was supported by the National Institute of Mental Health and other funding partners.

Beckett, J. O. S., Buzdygon, R., Nguyen, S., Clark, A. A., Schalk, S. S., Svanholm, L. E. H., Brasher, T. J., Bazin, M., Cuccurazzu, B., Halberstadt, A. L., McCorvy, J. D., & Mascal, M. (2025). Transforming Amino Acids into Serotonin 5-HT 2A Receptor Ligands Using Photochemistry. Journal of the American Chemical Society, 147(52), 48400–48415. https://doi.org/10.1021/jacs.5c19817

Psychedelic compounds such as psilocybin and LSD are known to act on the 5-HT2A receptor in the brain. Activation of this receptor has been linked to changes in perception as well as to neural plasticity, which may underlie therapeutic effects observed in depression, post-traumatic stress disorder and substance-use disorders. However, the intense perceptual alterations associated with these drugs present regulatory and clinical challenges. Identifying molecules that retain beneficial signaling properties while minimizing hallucinogenic effects is therefore a major focus in neuropharmacology.

Professor Mark Mascal from University of California, Davis stated,

“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.

The UC Davis team approached the problem from a chemical design perspective. Rather than modifying existing psychedelic scaffolds, they explored whether entirely new molecular frameworks could be generated from simple biological building blocks. The researchers combined various amino acids with tryptamine, a metabolite derived from tryptophan. The resulting intermediates were then exposed to ultraviolet light, triggering photochemical rearrangements that reshaped them into structurally distinct compounds.

This light-driven transformation enabled the rapid creation of a library of candidate molecules. According to study authors Joseph Beckett and Trey Brasher, doctoral researchers in the Mascal laboratory, the method provides a relatively straightforward and environmentally conscious synthetic route compared with multi-step traditional approaches often required in medicinal chemistry.

Computational modeling was used to screen approximately 100 newly generated compounds for predicted binding at the 5-HT2A receptor. From this group, five molecules were selected for laboratory testing. In cell-based assays, the candidates demonstrated varying degrees of receptor activation, with measured efficacies ranging from moderate to near full agonist activity.

One compound, referred to as D5 in the study, displayed activity consistent with a full agonist at the 5-HT2A receptor. In receptor pharmacology, a full agonist is capable of eliciting the maximum biological response achievable through that signaling pathway. Based on this property, the team anticipated that D5 might produce behavioral effects similar to known psychedelics.

To evaluate this possibility, the compound was administered to mice. Researchers assessed the head-twitch response, a widely used behavioral proxy for hallucinogenic activity in rodents. Despite robust receptor activation in vitro, D5 did not induce the head-twitch response. In some observations, psychedelic-like behaviors were reduced rather than enhanced.

This divergence between receptor activation and behavioral outcome suggests a more nuanced relationship between serotonin signaling and hallucinogenic effects than previously assumed. Laboratory and computational findings indicate that the new scaffold can engage signaling pathways associated with both neural plasticity and perceptual alterations. However, downstream modulation within the brain may suppress or alter specific responses.

The researchers propose that interactions with other serotonin receptor subtypes or signaling biases within the 5-HT2A pathway could explain the absence of hallucinogenic-like behavior. Biased agonism, in which a compound preferentially activates certain intracellular pathways over others, has become an area of increasing interest in drug development. If D5 or related molecules favor plasticity-related pathways while limiting those associated with altered perception, they may represent a distinct pharmacological profile.

The work aligns with a broader movement in psychedelic research toward next-generation compounds designed to separate therapeutic potential from subjective effects. Several academic groups and biotechnology firms are investigating modified psychedelics or non-hallucinogenic analogs aimed at improving safety, dosing flexibility and clinical scalability.

What differentiates the UC Davis study is its focus on creating an entirely new therapeutic scaffold rather than incrementally modifying known psychedelic molecules. In medicinal chemistry, most advances stem from adjusting existing chemical backbones to fine-tune pharmacology. Completely new scaffolds are comparatively rare because they require both synthetic innovation and pharmacological validation.

The photochemical strategy used here expands the chemical space available for serotonin-targeting agents. By leveraging light as a tool to reorganize amino acid derivatives, the team demonstrated a modular route for generating structurally diverse molecules. This approach could be applied to other receptor systems beyond serotonin.

Future studies will examine the precise signaling pathways engaged by D5 and related compounds. Detailed mapping of receptor interactions and intracellular cascades may clarify why behavioral hallmarks of psychedelics were absent despite receptor activation. Additional preclinical work will be required to evaluate safety, durability of effects and therapeutic relevance.

From an engineering standpoint, the research illustrates how advances in synthetic methodology can open new directions in neuropharmacology. The combination of photochemistry, computational screening and receptor biology provides an integrated framework for drug discovery.

While translation into clinical use remains a longer-term objective, the findings contribute to a growing body of evidence that receptor activation alone does not dictate behavioral outcome. By identifying molecules that engage serotonin pathways without inducing overt hallucinogenic behavior in animal models, the UC Davis team has introduced a potential path toward brain-active therapeutics with a different risk profile.

As the field of psychedelic-inspired medicine continues to evolve, the ability to design and test new scaffolds efficiently may play a central role in expanding treatment options for mood and substance-use disorders.