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Development of Novel Therapeutic for Parkinson’s Disease

(S. Kortagere, J. Schneider)

Abstract: Parkinson's disease (PD) can be considered as a multi-system disorder affecting the regulation of several neurotransmitters in the brain. Most significantly, the dopaminergic and noradrenergic terminals are lost due to neuro-degeneration and so levodopa (marketed as Sinemet or Parcopa) still remains the gold standard therapy for PD. However, long-term therapy with levodopa leads to levodopa induced dyskinesias (LID) that cause painful abnormal involuntary movements. A novel therapeutic that can modulate the levels of both dopamine (DA) and norepinephrine (NE) would be essential to systemically alleviate the motor and non-motor symptoms of PD. To test this therapy, this team has designed and developed a dual acting compound, PEUN3 that inhibits the NE transporter (NET) and is a potent D3 receptor agonist. In accordance with their hypothesis, PEUN3 does not induce desensitization in either D2 or D3 receptors, and significantly reduces abnormal involuntary movements when used adjunctively with L-dopa. In addition, PEUN3 used together with L-dopa significantly improved reversal of the motor deficit in 6-0HDA-lesioned rats compared to the L-dopa response alone. These preliminary results suggest that PEUN3 with its dual effect as a NET inhibitor and D3 agonist would be highly suitable to treat motor and non-motor symptoms of PD. Based on these promising preliminary findings, the team has embarked on a series of preclinical optimization studies that will further develop PEUN3 as a novel therapeutic for PD with or without LID. These include 1) Complete pre-clinical pharmacological profiling of PEUN3 2) Screening ofPEUN3 in a non-human primate model of PD using cynomolgus monkeys for effects on PD and LID symptoms. The expected outcome is the pre-clinical optimization of PEUN3 as a novel, monoaminergic modulator that can be used alone or in conjunction with Ldopa to provide improved management of both motor and non-motor symptoms of the PD patient. With the successful completion of these studies, the team intends to deliver a potential lead candidate for first in-human studies.

This technology is licensed to PolyCore Therapeutics, LLC. Please contact Robert McGrath for an introduction to Kelly Beck, CEO of Polycore.