1. Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques.
- Author
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Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, Reynolds IJ, Ravenscroft P, Hill M, Fox SH, Brotchie JM, Laufer R, and Hayden MR
- Subjects
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Brain diagnostic imaging, Brain metabolism, Dyskinesia, Drug-Induced etiology, Macaca fascicularis, Parkinsonian Disorders chemically induced, Positron-Emission Tomography, Receptor, Muscarinic M2 metabolism, Receptor, Serotonin, 5-HT1A metabolism, Receptor, Serotonin, 5-HT2A metabolism, Receptors, Adrenergic, alpha-2 metabolism, Receptors, Dopamine D2 metabolism, Receptors, Dopamine D3 metabolism, Receptors, Histamine H3 metabolism, Receptors, sigma metabolism, Sigma-1 Receptor, Antiparkinson Agents adverse effects, Dyskinesia, Drug-Induced drug therapy, Levodopa adverse effects, MPTP Poisoning drug therapy, Movement drug effects, Parkinsonian Disorders drug therapy, Piperidines pharmacology
- 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 σ
1 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., (© 2018 International Parkinson and Movement Disorder Society.)- Published
- 2019
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