The UC Davis team is developing a new class of drugs with a serotonin effect

The UC Davis team is developing a new class of drugs with a serotonin effect

Researchers at UC Davis have developed a new method that uses light to convert amino acids - the building blocks of proteins - into molecules similar in structure to psychedelics and mimicking their interaction with the brain. Like psychedelics, these molecules activate the brain's serotonin 5-HT2A receptors, which promote the growth of cortical neurons, and could be candidates for treating a variety of brain disorders, such as depression, substance use disorders and PTSD. However, they do not trigger typical hallucinogenic behavior in animal models.

The research was recently published in the Journal of the American Chemical Society.

"The question we were trying to answer was, 'Is there a whole new class of drugs in this field that hasn't been discovered yet?'" 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 research opens the door to an optimized and environmentally friendly drug discovery platform for new serotonin-targeting drugs that provide the benefits of psychedelics without significantly distorting perception.

“It's very typical in medicinal chemistry to take an existing scaffold and make modifications that tweak the pharmacology a little bit in one way or another,” said study author Trey Brasher, also a graduate student. Student in the Mascal Lab and member of the IPN. "But especially in the psychedelic field, completely new scaffolds are incredibly rare. And this is the discovery of a completely new therapeutic framework."

Discovering a new therapeutic framework

The researchers created a library of potentially therapeutic molecules by coupling various amino acids with tryptamine, a metabolite of the essential amino acid tryptophan. They then irradiated these molecules with ultraviolet light to convert them into new compounds with medicinal value.

Computer simulations were used to test the binding affinity of 100 of these compounds to the 5-HT2A receptor.

Five candidates were selected for further laboratory testing to determine potency and effectiveness. The effectiveness of the selected compounds ranged from 61% to 93%, with the latter representing a complete agonist - a compound capable of eliciting the maximum biological response of the 5-HT2A system.

The team designated the full agonist in the group as D5. They expected that administering the compound to mouse models would result in head twitch responses, a hallmark of hallucinogenic behaviors.

However, this was not the case. Although D5 fully activates the same receptor as psychedelics, it did not trigger head twitch reactions.

“Laboratory and computational studies have shown that these molecules can partially or fully activate serotonin signaling pathways associated with both brain plasticity and hallucinations, while experiments in mice showed suppression of psychedelic responses rather than their induction,” said Beckett and Brasher.

Next steps: Why no hallucinations?

The team plans to conduct follow-up studies to better understand whether other serotonin receptors in the brain modulate or suppress the hallucinogenic effects of D5.

We found that the scaffolding itself has a number of activities. But now the challenge is to elucidate this activity and understand why D5 and similar molecules are not hallucinogenic when they are full agonists.”

Trey Brasher, University of California-Davis

Additional authors of the article include Mark Mascal and Lena EH 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 described here was funded by grants from the National Institutes of Health and the Source Research Foundation.

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