Parkinson?s disease (PD) is a neurodegenerative disorder characterized by severe motor deficits caused by the progressive loss of striatal dopamine (DA) input and it is commonly treated with the DA precursor L-DOPA or by DA D2 receptor (D2R) agonists. Although L-DOPA ameliorates the motor deficits, prolonged use leads to motor abnormalities, termed L-DOPA-induced dyskinesias. Despite these limitations, L-DOPA is the mainstay for PD treatment. Various animal models of PD suggest that dyskinesias are associated with enhanced G-protein mediated signaling at DA receptors (DARs) and this leads to changes in gene expression and uncontrolled neuronal excitability. Research over the past decade has shown that DARs can signal not only through G-proteins, but also also through ?- arrestin2 (?arr2) scaffolds containing signaling complexes that initiate intracellular signals distinct from those of G- proteins. Recently we have demonstrated in PD models that over-expression of ?arr2 in the striata of mouse, rat, or macaque reduces L-DOPA-induced dyskinesias. This novel approach facilitated locomotion and simultaneously desensitized G-protein signaling, thereby reducing the dyskinesia without potentially affecting other neurotransmitter systems. The Overall Goal of the proposed research is to provide preclinical results for taking novel D1R and D2R ?arr-biased compounds into clinical PD trials. Our Central Hypothesis is that small molecule drugs that selectively activate the ?arr, but not the G-protein, pathway at D1Rs/D2Rs will have anti-parkinsonian activities without inducing dyskinesias. We have three Specific Aims.
Aim 1 will develop ?arr-biased D1R and D2R ligands from the leads/hits we recently discovered.
Aim 2 will assess the in vitro profile of the newly synthesized ?arr-biased compounds.
Aim 3 will determine the in vivo effects of D1R and D2R ?arr-biased compounds in animal models of PD.
We will exploit our success in developing ?arr-biased D2R compounds and will use this experience in developing ?arr-biased D1R and D2R compounds. With this unique approach we should dissociate normal motor function from dyskinesias. Collectively, our studies should identify novel compounds that can be taken into PD clinical trials.
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