This new molecule, called JRT, has potential applications to treat neuropsychiatric diseases in ways that have not previously been possible
By MADELINE HASS — science@theaggie.org
A team of UC Davis researchers within the Olson Lab, run by David E. Olson, has synthesized a new molecule named JRT that has the potential to treat neuropsychiatric diseases. This molecule is an analogue of lysergic acid diethylamide (LSD) with reduced hallucinogenic potentials yet many therapeutic properties, making it an outstanding candidate for treating conditions like schizophrenia.
The creation of this new molecule was accomplished over a five-year process, and it consisted of transposing two atoms within LSD that lowered the potential of producing hallucinogenic responses in humans. This molecule’s close relation to LSD allows it to contain many plasticity-producing aspects and the ability to promote cortical neuron growth, both of which are necessary in the treatment of neuropsychiatric diseases.
Cassie Hatzipantelis, a postdoctoral scholar at the Institute for Psychedelics and Neurotherapeutics and key member of the study, spoke on the creation of this new JRT molecule.
“Lee Dunlap, along with many people in the chemical field, had identified this key interaction [in LSD] between the tryptamine core structure and the 2A receptor — this serine residue. He made this version of the molecule where you just take the nitrogen and you put it somewhere else,” Hatzipantelis said. “After this, it can’t make that interaction anymore, and it completely obliterates the hallucinogenic potential of the molecule.”
Before testing JRT’s therapeutic potential, the team focussed on confirming that this drug would not have the potency of hallucinogenic potential that is associated with LSD. The first step in this process was to create a general characterization of the molecule on the cellular level.
The team utilized a biosensor assay that they developed, called pyschLight, that will show if a drug is predicted to be hallucinogenic or not based on a fluorescence indication. Hallucinogenic and non-hallucinogenic ligands within molecules will bind to pyschLight and showcase different fluorescence profiles.
“We know that hallucinogenic drugs versus non hallucinogenic drugs will induce a different confirmation; they kind of change in a slightly different way, so when this lights up we can say this will most likely be hallucinogenic,” Hatzipantelis said. “We found that LSD has a really high response and is incredibly potent, but our compound JRT was far less potent and way less active so it was predicted at this stage to be non-hallucinogenic.”
After confirming the reduced hallucinogenic potentials on the cellular level, the team moved to confirming this with a biological correlation. This was done via a study conducted on mice, which entailed giving each drug to a mouse and overseeing a head twitch response test, a famous method to test a drug’s hallucinogenic potency.
“We know that when you give a hallucinogenic drug to a mouse, they have this very stereotypical head twitch,” Hatzipantelis said. “And we know that the potency of a drug in a mouse head twitch is a near perfect correlation with the potency of the drug with its hallucinogenic potency in humans.”
Yara Khatib, a fourth-year Ph.D. candidate and member of the Olson Lab, further commented on this part of the study.
“We found that when we tested JRT and compared it to LSD, there was a very significant reduction in the number of head twitches that we have,” Khatib said. “We saw the same number of head twitches you would see when giving a mouse just a normal saline injection, so that was really encouraging to us.”
Neuropsychiatric diseases have a wide range of indicators that are categorized into positive symptoms, negative symptoms and cognitive symptoms. Current antipsychotic medicines have shown success in treating the positive symptoms of these conditions, such as hallucinations and delusions yet have not been successful in treating cognitive or negative symptoms.
Defining features of the negative and cognitive symptoms are morphological and synaptic deficits. So, one of the next steps of the team was to test the therapeutic properties of JRT, they wanted to see if it had the plasticity-promoting aspects and ability to cause cortical neuron growth that they had hypothesized, as well as the ability to treat many of the other aspects of negative and cognitive symptoms associated with neuropsychiatric diseases.
“For this process, we literally give the drug and then count the neurons,’” Hatzipantelis said. “We can see if the neurons get really complex and count how many branches and how many spines they have, how many synapses and if their synapses are functional. A whole suite of structural and functional plasticity experiments are done to really assess if this is happening or not, and JRT was seen to be one of the strongest plasticity-promoting compounds we’ve ever tested.”
Another test that was done was a sucrose preference test as part of the behavioral assay, in order to see if JRT could combat the symptom of loss of pleasure symptom, which is commonly seen in neuropsychiatric diseases. It consisted of first testing initial preference for sugar water in mice, then inducing a depressive model in them before administering JRT to see if it could restore their desire to drink this sugar water.
“It was a one-month process of working with the animals and seeing how their preferences change. After administering the JRT, we could see that the drug was able to restore their preference,” Khatib said. “It also had the ability to maintain that for weeks after. 10 days later, I set up the study again and saw that the mice with the JRT still preferred the sugar water relative to the animals that remained in their depressive state.”
There is still much work to be done before JRT can see wide-scale use or application, yet the creation of it alone is groundbreaking work. It showcases that there is a way to lower the hallucinogenic properties while harnessing many of the positive properties of certain drugs, a discovery that will prove very useful as time moves forward.
“It’s a proof of concept that we can change the direction of drug development and the way that we approach the treatment of these conditions and maybe even make more scalable treatments that can reach a more sizable population,” Khatib said.
Written by: Madeline Hass— science@theaggie.org
