Dopamine D3 receptor ligand suppresses the expression of levodopa-induced dyskinesia in nonhuman primate model of parkinson's disease

Thomas Oh,Elyas S Daadi,Jeffrey Kim,Etienne W Daadi,Peng-Jen Chen,Gourav Roy-Choudhury,Jonathan Bohmann,Benjamin E Blass,Marcel M Daadi

doi:10.1016/j.expneurol.2021.113920

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.

Highlights

Parkinson’s disease (PD) is a relentlessly progressive neurodegenerative disorder impacting millions of people worldwide currently categorized as an eminent noninfectious pandemic [1]
We have identified a potent dopamine D3 receptor (D3R) ligand, PD13R that is highly selective for the D3R over other dopamine receptors
The lack of selectivity for D2R caused by the impairment of hydrogen bonding in the amide group of PD13R leads to a solvation penalty [30] not present in the on-target D3R

Summary

Introduction

Parkinson’s disease (PD) is a relentlessly progressive neurodegenerative disorder impacting millions of people worldwide currently categorized as an eminent noninfectious pandemic [1]. PD pathology is associated primarily with the death of dopamine neurons in the substantia nigra and manifests with motor and non-motor dysfunctions including tremor, bradykinesia, rigidity, cognitive deficits and sleep disturbances [4,5,6,7,8,9,10] These symptoms are managed by dopamine-replacement pharmacological treatments that enhance dopamine in the striatum with the dopamine precursor L-3,4-dihydroxy-phenylalanine (levodopa). Over 80% of parkinsonian patients treated with levodopa develop levodopa-induced dyskinesia after five years [16, 17] These debilitating side effects spurred the discovery of alternative dopamine-replacement pharmacological treatments dopamine receptor agonists and inhibitors of enzymes that degrade dopamine and the new antidyskinetic drug in use today, amantadine. The loss of DBS benefit parallels the progressive degenerative changes associated with PD

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Conclusion