Levodopa-induced dyskinesia is a major dose-limiting effect associated with long-term treatment of Parkinson’s disease (PD). There are no effective treatments for either preventing the development or reversing levodopa-induced dyskinesia in PD. To this end, the objective of this project is the optimization of selective dopamine 4 (D4) receptor antagonists for the treatment of dyskinesia. The study of D4 has been relatively neglected even though the D4 receptor is within the basal ganglia.
We plan to study the effects of a potent and selective D4 receptor antagonist in a preclinical model of levodopa-induced dyskinesia.
Our group will improve and optimize our initial lead compound and test the optimized compounds for D4 receptor activity and binding. Next, we will evaluate our leading compounds in an in vivo pharmacokinetic assay. Lastly, we will take the best-in-class compound into a pre-clinical model of levodopa-induced dyskinesia in order to establish the efficacy of a novel and selective D4 receptor antagonist.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
If selective D4 receptor antagonists are a potential therapeutic approach, they may be able to ease levodopa-induced dyskinesia and improve quality of life for people with Parkinson’s disease.
Next Steps for Development:
At the completion of this study, we will possess potent and selective D4 receptor antagonists with favorable properties that have shown efficacy in a pre-clinical model. This will lead to the development of novel drug candidates that can be tested in patients.