Molecule Safely Eases Dyskinesia Tied to Levodopa in Primate Model
A newly discovered oral molecule, called PD13R, significantly lessened levodopa-induced dyskinesia, its involuntary and jerky movements, while maintaining the therapy’s benefits in a non-human primate model of Parkinson’s disease.
Notably, in contrast to Gocovri (amantadine) — an approved therapy to treat levodopa-induced dyskinesia — PD13R did not affect the animals’ sleep, suggesting this new molecule may be a safer as well as effective in treating dyskinesia, the researchers noted.
“We were very excited to see the robust antidyskinetic effect of [PD13R],” Marcel Daadi, PhD, the study’s senior author and an associate professor at Texas Biomedical Research Institute (Texas Biomed), said in an institute press release.
Researchers now plan to complete the preclinical safety and efficacy studies required by the U.S. Food and Drug Administration before the therapy can be tested in people, with a goal of beginning a Phase 1 trial within two years.
Their study, “Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of Parkinson’s disease,” was published in the journal Experimental Neurology.
Levodopa, a mainstay Parkinson’s treatment, is a precursor of dopamine, the brain chemical messenger progressively lost in patients and essential for muscle control. Despite its efficacy at easing motor symptoms, levodopa’s long-term use is associated with the development of dyskinesia.
“Levodopa is amazing, it works like magic, but it has side effects,” Daadi said, adding that “if we can eliminate these side effects, it could change the life of patients with Parkinson’s.”
While amantadine (brand names include Gocovri, Symmetrel, Osmolex ER) is approved to treat levodopa-induced dyskinesia, it is often accompanied by side effects such as cardiovascular problems, insomnia, anxiety, and hallucinations.
“The search for better anti-dyskinetic agents remains a critical medical need,” the researchers wrote.
Daadi and his team at Texas Biomed, along with colleagues at Southwest Research Institute (SwRI) and Temple University, provided evidence that a newly discovered molecule, PD13R, may be as effective as amantadine while causing fewer side effects.
PD13R is an orally available small molecule designed to selectively bind to a dopamine receptor called D3 receptor (D3R), whose levels are increased in motor-related brain regions with prolonged levodopa treatment and associated dyskinesia.
As such, D3R is thought to be involved in the development of levodopa-induced dyskinesia and “may represent a viable therapeutic target for its treatment,” the researchers wrote.
The compound was identified through SwRI’s drug discovery software Rhodium and produced by medicinal chemists at Temple.
Daadi and his team then evaluated PD13R’s selectively across all five dopamine receptors. The researchers found it had a 1,486-times higher selectivity for D3R than for D2R, the dopamine receptor with the most similar structure to D3R.
Notably, improving s compound’s selectivity for D3R over D2R “has been the most challenging aspect in developing selective D3R [targeting molecules],” the team wrote.
Further analysis showed that, in addition to its potency and selectively, PD13R also has a favorable half-life, or the time it takes for its initial dose to be reduced by half in the body.
Next, the researchers assessed the molecule’s effects on a non-human primate model of Parkinson’s and levodopa-induced dyskinesia. The animals — marmosets, a monkey species — wore activity/sleep monitors, and their dyskinesia and Parkinson’s symptoms were assessed with validated measures.
Adding PD13R to their levodopa treatment eased the animals’ dyskinesia by about 85% and significantly lessened their Parkinson’s motor symptoms, such as tremors, slowness of movement, uncoordinated movement, and hyperactivity.
Notably, the researchers found that these effects were similar to those observed when the marmosets were given amantadine in combination with levodopa. However, amantadine was associated with a significant increase in nocturnal activity and poorer sleep, while PD13R did not affect the animals’ sleep.
“The anti-dyskinetic effects of PD13R didn’t affect the anti-parkinsonian benefits of levodopa while improving sleep efficiency compared to amantadine,” the researchers wrote.
“Our future studies are aimed at optimizing and developing the lead compound PD13R for treating patients with Parkinson’s disease,” the team concluded.