Pridopidine, a clinic‐ready compound, reduces 3, 4‐dihydroxyphenylalanine‐induced dyskinesia in Parkinsonian macaques. Issue 5 (21st December 2018)

• Record Type: Journal Article
• Authors: Johnston, Tom H.; Geva, Michal; Steiner, Lilach; Orbach, Aric; Papapetropoulos, Spyros; Savola, Juha‐Matti; Reynolds, Ian J.; Ravenscroft, Paula; Hill, Michael; Fox, Susan H.; Brotchie, Jonathan M.; Laufer, Ralph; Hayden, Michael R.
• Is Part Of: Movement disorders. Volume 34:Issue 5(2019)
• Page Start: 708
• Page End: 716
• Publication Date: 2018-12-21
• Subjects: dopidines -- dyskinesia -- Parkinson's disease -- sigma‐1 receptor; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.27565
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: Background: Pridopidine, in development for Huntington's disease, may modulate aberrant l ‐dopa‐induced effects including l ‐dopa‐induced dyskinesia (LID). Objective: This study investigated whether pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. Methods: The pharmacokinetic profile and effects of pridopidine (15‐30 mg/kg) on parkinsonism, dyskinesia, and quality of on‐time, in combination with l ‐dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ1 and dopamine D2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. Results: Pridopidine produced a dose‐dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on‐time with disabling dyskinesia evoked by l ‐dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti‐parkinsonian benefit of l ‐dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20‐30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic‐α2C, dopamine‐D3, and serotoninergic‐5‐HT1A sites) to a higher degree than D2 and might contribute to the antidyskinetic actions. Conclusions: In MPTP macaques, pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l ‐dopa. Although the actions of pridopidine were associated with full σ1 occupancy, effective exposures are more likely associated with occupancy of additional, non‐sigma receptors. This complex pharmacology may underlie the effectiveness of pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society