Researchers at Texas Biomedical Research Institute have identified a molecule that showed promise in reducing a key symptom associated with Parkinson’s disease: Dyskinesia, or uncontrollable muscle spasms. The results of their 2022 study were published in Experimental Neurology.
Dyskinesia in Parkinson’s Disease
Dyskinesia is not a symptom of Parkinson’s disease by itself. Rather, it is caused by a Parkinson’s medication called levodopa. Levodopa is considered to be the mainstay of treatment for Parkinson’s disease and is very effective at controlling symptoms, but its principal side effect is involuntary muscle spasms, which typically appear several years after starting treatment.
Other therapies exist to manage dyskinesia, but new contenders are always being sought out. This newly researched drug could replace conventional treatment options for dyskinesia and perhaps even make it into the standard Parkinson’s disease treatment toolkit.
Led by Marcel Daadi, PhD, associate professor at Texas Biomed, the study’s researchers had the goal in mind of locating a compound that binds to a certain dopamine receptor–the D3 receptor. Dopamine–or, rather, the lack of it–plays an important role in Parkinson’s disease, and has been implicated in Parkinson’s disease-associated dyskinesia. It’s thought that levodopa causes fluctuations in dopamine levels, which in turn leads to dyskinesia.
However, there are five different types of dopamine receptors, and the team needed to target only the D3 receptor. To accomplish this, Daadi and his team collaborated with the Southwest Research Institute, known for its drug discovery software Rhodium. The software was able to assist the team in identifying a potential drug candidate that targeted only the D3 receptor. Rhodium also identified the potential drug’s mechanism of action (how it could bind to the D3 receptor).
The drug candidate, a molecule named PD13R, was found to bind to the D3 receptor with a 1,486-times greater selectivity than for the D2 receptor, which is structurally similar to D3.
The final step was to test the effects of PD13R in animal subjects with Parkinson’s disease, specifically marmosets, a type of monkey. The marmosets had been given levodopa and, like a human with Parkinson’s disease would, had subsequently developed dyskinesia. However, once administered PD13R, the marmosets showed a significant reduction in symptoms.
After witnessing the promising results, the team decided to continue pursuing PD13R for its use in Parkinson’s disease-associated dyskinesia. “I am very hopeful we can move this into Phase 1 clinical trials within two years,” said Daadi. Daadi plans to conduct eventual clinical trials in humans with the compound, after completing the preliminary safety and efficiency studies required by the FDA.
Written by Natan Rosenfeld