In vivo characterization of a novel dopamine D3 receptor agonist to treat motor symptoms of Parkinson's disease

Synthetic dopaminergic agents have found utility in treating neurological and neuropsychiatric disorders since the beginning of 19th century. The discovery of Levodopa (l-dopa) to effectively treat motor symptoms of Parkinson's disease (PD) revolutionized the therapy and remains a gold standard for treating PD. However, l-dopa therapy has been implicated in worsening of the non-motor symptoms including cognition and long-term therapy leads to plasticity and development of abnormal involuntary movements (AIMs) that are collectively called l-dopa induced dyskinesias (LID). Studies in rodents and non-human primates with PD have supported a role for dopamine D3 receptors in the etiology of both the motor symptoms and LID. We have recently developed SK609, a selective dopamine D3 receptor agonist with atypical signaling properties. In this study, we further characterized this novel small molecule using the unilateral lesioned rodent model of PD. In the forepaw stepping test paradigm, SK609 significantly improved the performance of the impaired paw and also normalized the bilateral asymmetry associated with the hemiparkinson rat. In addition, a chronic treatment of SK609 did not induce any AIMs and when used adjuvantly with l-dopa significantly reduced AIMs induced by l-dopa. Further, an optimal dose combination of SK609 with l-dopa was determined by dose dependent titrations of both SK609 and l-dopa that produced minimal AIMs and maximized the effect on improving motor symptoms. Results from this study suggest that SK609 is a novel dopaminergic agent that has the therapeutic potential to treat PD and LID. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.

Abnormal involuntary movements; Adjuvant therapy; Agonist; Dopamine D3 receptor; Optimal therapy; Parkinson's disease; Pharmacokinetics; Stepping test; l-dopa induced dyskinesia.