Promising Outcomes of Original Grant:
In our original proposal, we identified two chemical scaffolds (protein support structures) as dopamine receptor 4 (D4R) antagonists (compounds that block the activity of dopamine) and optimized their strength and ability to pass into the brain. We then tested the lead molecule in a pre-clinical model of L-DOPA-induced dyskinesias (LIDs), disabling involuntary movements caused by long-term use of levodopa for Parkinson's disease (PD), and showed that the compound was able to reverse the LIDs.
Objectives for Supplemental Investigation:
During the supplemental funding period, our lab will further optimize the lead compound identified during the original funding period. The original compound was an important proof-of-concept molecule and further refinement in its strength, selectivity and pharmacokinetic properties (oral dosing) will be investigated during the supplemental period. A potential outcome of this period would be identification of a compound that could potentially lead to a novel treatment for LIDs.
Importance of This Research for the Development of a New PD Therapy:
As there are no effective treatments for PD-LIDs, this work could lead to a novel, first-in-class therapy. We will optimize our identified compounds and look at initial safety assessments in order to better evaluate our lead molecules. Work from this funding period is expected to deliver a novel compound that may progress into pre-clinical testing.