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.