Highlights
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Dyskinesia is a debilitating side effect of levodopa, the mainstay pharmacotherapy for Parkinson’s disease.•
Attenuating dyskinesia has been a significant challenge in the clinical management of Parkinson’s disease.•
The dopamine D3 receptor is involved in the pathogenesis of motor complications and levodopa-induced dyskinesia.•
We discovered PD13R, a dopamine D3 receptor ligand with an arylpiperazine pharmacophore and desirable drug-like properties.•
PD13R eliminated levodopa-induced dyskinesia and improved Parkinson’s disease-like symptoms in a nonhuman primate model.
Abstract
Parkinson’s disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained 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 within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.
