Study Rationale: L-DOPA is the primary drug used for treating the mobility loss that occurs in Parkinson’s disease (PD) due to decreases in dopamine. Although L-DOPA enhances mobility, chronic administration induces abnormal movements termed dyskinesias. Dyskinesias are caused by imbalances in signaling via an important target of brain dopamine, the D1 receptor. A drug that could rebalance D1 receitpr activation by favoring a type of signaling that recruits arrestin proteins, which modulate D1 receptor activity, would decrease the side effects of L-DOPA treatment and facilitate the retention of normal mobility without inducing dyskinesias in people with PD.
Hypothesis: Our hypothesis is that a drug that can steer D1 receptor activation towards the arrestin protein signaling pathway will facilitate the retention of normal mobility without dyskinesia in people with PD undergoing chronic L-DOPA therapy.
Study Design: We plan to identify new compounds that can preferentially activate the arrestin pathway of the dopamine D1 receptor, as opposed to the alternative G-protein pathway, which is associated with dyskinesias. To identify these compounds, we will search through millions of structures in a database of drug-like molecules using state-of-the computer algorithms that predict their binding to the D1 receptor at sites that change D1 receptor activity. Those compounds that meet criteria that are consistent with good drug design will be optimized into lead candidates and tested in preclinical models for the ability treat PD symptoms with fewer dyskinesia side effects.
Impact on Diagnosis/Treatment of Parkinson’s disease: The drugs we plan to develop will reduce, delay or prevent the dyskinetic movements that occur commonly with chronic L-DOPA therapy. Such drugs will prolong the effectiveness of L-DOPA treatment in enabling normal movement and thereby improve the quality of life of people with PD.
Next Steps for Development: The next preclinical development phase will require testing of oral dosing, toxicity and efficacy in animal models followed by scaling production of the lead or backup compounds prior to submission of an Investigational New Drug application.