Pridopidine, a clinic‐ready compound, reduces 3,4‐dihydroxyphenylalanine‐induced dyskinesia in Parkinsonian macaques
Bibliographic record
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 σ 1 and dopamine D 2 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 σ 1 occupancy (>80%), suggesting that σ 1 engagement alone is unlikely to account for the antidyskinetic benefits of pridopidine. Exposures following effective doses (20‐30 mg/kg), while providing full σ 1 occupancy, provide only modest dopamine D 2 occupancy (<40%). However, effective pridopidine doses clearly engage a range of receptors (including adrenergic‐α 2C , dopamine‐D 3 , and serotoninergic‐5‐HT 1A sites) to a higher degree than D 2 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 σ 1 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
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".