Pre-clinical Validation of a Novel Target for Dyskinesia Induced by Levodopa

Study Rationale:
The motor symptoms associated with Parkinson’s disease (PD) are treated by replacing dopamine, the brain chemical that is lost when dopamine-producing neurons die. Initially, treatment with the compound levodopa improves motor control; however, chronic use leads to the development of abnormal involuntary movements known as levodopa-induced dyskinesia (LID), which can be as debilitating as the disease itself. Dyskinesias arise when activity in a brain region called the striatum becomes unbalanced, promoting excessive movement. Here, we will determine whether targeting a novel protein that is well positioned to limit striatal dysfunction can prevent LID without triggering other unwanted side effects.

Hypothesis:
We hypothesize that activation of this target — a specific G-protein coupled receptor (GPCR) — will restore the balance to striatal pathways that is disturbed by treatment with levodopa, thereby reducing dyskinesia without sacrificing the anti-parkinsonian benefits of levodopa.

Study Design:
This study will test the effectiveness of modulating target GPCR activity in two pre-clinical models of LID. Initial tests will validate the efficacy of targeting this novel GPCR. Following successful validation, a series of novel compounds will be synthesized and tested for their ability to regulate the target GPCR. These compounds will then be thoroughly vetted to ensure they are specific for the target, confirm they can effectively modulate the activity of striatal circuits and fully assess their pharmacokinetic properties. A single lead compound will be identified, tested and undergo initial toxicity screening and formulation, in preparation for clinical studies.

Impact on Diagnosis/Treatment of Parkinson’s Disease:
The strategy to modulate the activity of this novel GPCR could prove effective for balancing striatal activity at the level of neuronal circuits, thereby alleviating LID in people with PD who are taking levodopa.

Next Steps for Development:
Additional studies will be performed with the clinical lead compound to enable an investigational new drug (IND) application with the U.S. Food and Drug Administration, in preparation for clinical trials in individuals with PD.