Abstract Details

Title Novel class of compounds for the treatment of levodopa-induced dyskinesia

Topic Movement Disorders

Presentation(s) P7 - Poster Session 7 (8:00 AM-9:00 AM)

Poster/Presentation
Number 5-003

Objective The goal of this study was to screen a novel series of anti-dyskinetic compounds, with an arylpiperazine-based pharmacophore, that are highly selective for the dopamine D3 receptor (D3R).

Background Parkinson’s disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. Since its discovery in the 1961, levodopa remains the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia (LID) within 5 years of therapy.

Design/Methods We initially conducted a docking simulation to identify highly selective compounds for the D3R. Selected compounds were tested in the in vitro competitive D3R and D2R radioligand binding assays, in microsomes stability assay, in vitro ADME and in vivo pharmacokinetic. The in vivo pharmacology was evaluated in the marmoset model of PD expressing LIDs.

Results We have identified a novel D3R ligand that treated motor symptoms and reduced dyskinesia by 80% in the nonhuman primate (NHP) model of Parkinson’s disease exhibiting LID in response to levodopa treatment. The lead compound PD13R is G protein-biased partial agonist highly selective to D3R in comparison to the other dopamine receptors (D1R, D2R, D4R and D5R), orally active with desirable drug-like properties, including potency, selectivity and bioavailability. The anti-dyskinetic effects of PD13R were similar to amantadine. Interestingly, PD13R did not affect sleep efficiency, while amantadine significantly increased nocturnal activity and decreased sleep efficiency.

Conclusions This study suggests that D3R is a promising target for treating dyskinesia and that the arylpiperazine class of pharmacophore is a favorable class of antidyskinetic ligands. Further studies are needed to better understand the anti-dyskinetic and anti-parkinsonian effects of the arylpiperazine versus other pharmacophores. Current studies are aimed at developing this lead compound for treating PD patients with dyskinesia.

Authors/Disclosures
Marcel Daadi, PhD (Texas Biomedical Research Institute) PRESENTER	The institution of Prof. Daadi has received research support from NIH. Prof. Daadi has received intellectual property interests from a discovery or technology relating to health care.
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