Abstract
l-DOPA-induced dyskinesia remains an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential antidyskinetic efficacy of 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine (l-745,870), a potent and selective dopamine D4 receptor antagonist with a good toxicology profile and an excellent safety and tolerability record in phase I/II clinical studies, for non-PD indications. Six macaques were rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration. After induction of stable and marked dyskinesia, animals were administered acute challenges of l-745,870 in combination with l-DOPA. To guarantee D4 selectivity at the doses used in the study, we determined the plasma, cerebrospinal fluid, and brain levels of l-745,870. Coadministration of l-745,870 (1 mg/kg) and l-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison with l-DOPA alone (P < 0.01). l-745,870 had no effect on the duration of antiparkinsonian benefit (ON-time) (P > 0.05). However, l-745,870 (1 mg/kg) significantly increased the duration of ON-time without disabling dyskinesia (+204%; P < 0.001) and decreased duration of ON-time with disabling dyskinesia compared with l-DOPA alone (−56%; P < 0.01). Brain levels of l-745,870 (∼600 ng/g) were within the range at which l-745,870 provides selective D4 receptor antagonism. Plasma levels were comparable with those demonstrated to be well tolerated in human studies. These data suggest that selective D4 receptor antagonists represent a potential therapeutic approach for l-DOPA-induced dyskinesia. It is noteworthy that l-745,870 has already undergone significant clinical development, has an excellent profile for a therapeutic candidate, and could be advanced rapidly to phase IIa clinical studies for dyskinesia in PD.
Footnotes
This study was supported by The Cure Parkinson Trust and Krembil Neuroscience Fund. P.H. was supported by fellowships from the Edmond J. Safra Philanthropic Foundation, Parkinson Society Canada, and the Canadian Institutes of Health Research.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- PD
- Parkinson's disease
- NHP
- nonhuman primate
- 5-HT1A
- 5-hydroxytryptamine type 1A
- CSF
- cerebrospinal fluid
- MS/MS
- tandem mass spectrometry
- ddH2O
- double distilled H2O
- AUC
- area under the curve
- CL
- clearance
- GP
- globus pallidus
- GPe
- GP pars externa
- GPi
- GP pars interna
- MPTP
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- PK
- pharmacokinetics
- SNr
- substantia nigra pars reticulata
- STN
- subthalamic nucleus
- RM
- repeated measures
- ANOVA
- analysis of variance
- veh
- vehicle
- ns
- not significant
- L-745,870
- 3-([4-(4-chlorophenyl)piperazin-1-yl]methyl)-1H-pyrrolo[2,3-b]pyridine
- JL-18
- 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido(2,3-b)(1,4)benzodiazepine
- A-381,393
- 2-(4-(3,4-dimethylphenyl)piperazin-1-ylmethyl)-1H-benzimidazole
- NGD 94-1
- 2-[4-[(2-phenyl-1H-imidazol-5-yl)methyl]-1-piperazinyl]-pyrimidine.
- Received April 16, 2012.
- Accepted May 21, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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