Most drugs designed to act like psychedelics start out as just one. Chemists take a molecule like psilocybin or LSD, make targeted chemical changes, and test whether the modified version still activates the same brain receptors. The search area has remained narrow for years.
The research team decided to ignore all existing psychedelic substances and start in a simpler place: amino acids found in everyday proteins.
They exposed those molecules to ultraviolet light and collected what came out. Something in that crop worked in a way no one expected.
Find new structures
This research comes from the University of California, Davis (UC Davis), where Dr. Joseph Beckett received his Ph.D. Students studying chemistry were pursuing simple questions.
“The question we were trying to answer was, ‘Are there completely new classes of drugs in this field that haven’t been discovered yet?'” Beckett said.
Most psychedelic-inspired drug designs start with an existing molecule, like psilocybin or LSD, and tweak the edges.
Beckett and his colleague Trey Brasher wanted something unprecedented. There are no borrowed structures. There is no existing scaffolding to reverse engineer.
built with light
To create new candidates, the research team focused on amino acids, the building blocks of proteins. They combined several substances with tryptamine, a small molecule produced in the body from the amino acid tryptophan. The mixture was then exposed to ultraviolet light.
That light caused chemical changes, breaking and rebuilding bonds, creating entirely new structures. Each compound had characteristics that chemists had never before captured on paper.
The entire method used common starting materials and a single benchtop light source. It is cleaner and faster than the reactions that most drug discovery pipelines rely on.
Select 5 winners
From the resulting library, the researchers modeled how strongly 100 compounds bind to the brain’s serotonin receptors (the same ones activated by classic psychedelics).
Previous research has suggested that this receptor is central to the brain plasticity effects that may underlie the therapeutic effects of psychedelics in conditions such as depression.
Five of the candidates modeled appeared strong enough for laboratory testing. How strongly they activated the receptor ranged from about 60% to more than 90%.
The top compounds drove the receptors to the maximum possible response – the same ceiling that classic psychedelics hit. The team labeled the compound D5.
the mice stayed still
Standard pharmacology says a full agonist of that receptor should make mice’s heads twitch. This is an abbreviation in the field for hallucinogen-like behavior, and is used to screen candidates from the hundreds of published experiments.
D5 fully activated the receptor and attacked it as strongly as classic psychedelics. The mouse didn’t twitch. Never. The expected behavior never appeared.
Not only was there no reaction, D5 actually suppressed the seizures that would otherwise occur. That was the part that stopped the team.
It was a full agonist for the receptors thought to cause trips, but behaved like a non-psychedelic. Until this experiment, no one had reported that combination from a brand new chemical scaffold.
No known chemical relationship
That difference makes this discovery important. Other groups have created modified versions of known psychedelic drugs that suppress hallucinations.
For example, a recent paper took that approach with ibogaine, a hallucinogen derived from an African shrub, and stripped it down to simpler non-hallucinogenic compounds.
These approaches start with an existing molecule and prune it. D5 starts from zero. Because the structure has no direct ancestor among classic psychedelics, Brasher described it as an entirely new therapeutic scaffold.
New items are rare in this corner of medicinal chemistry. Most nominations over the past decade have been tweaks and variations on existing themes.
Still a mystery
The researchers are still unable to explain why D5 is unable to cause the mice to twitch. Their working hypothesis is that other serotonin receptors in the brain may dampen the signals that normally trigger hallucinations, canceling them out before the hallucinations take hold.
It’s still a guess, not a measurement. The researchers’ next plan is to track which other brain receptors D5 touches.
The researchers hope their study will reveal how each receptor shapes its final effect and where the inhibition actually comes from.
what will change
If these results apply to future animal experiments, the impact on brain plasticizing drugs will become a reality.
Its receptors are the same ones involved in neuron growth. This is the kind of growth associated with recovery from depression in published clinical trials.
A drug that provides these effects without travel would be easier to administer at home, easier to test on a wider scale, and easier to give to patients who cannot safely take full-strength psychedelics.
The last group is large. For example, people with a history of mental illness are excluded from most current trials. Non-hallucinogenic full agonists could change who has access to this class of drugs.
This research also gives chemists a method. Combining amino acids and tryptamine and exposing the mixture to UV light is quick, inexpensive, and made from common ingredients. Other labs can run the same recipe with different inputs and generate their own suggestions.
This research Journal of the American Chemical Society.
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