Abstract
L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia remain an unmet challenge in the treatment of Parkinson's disease (PD). Here, we investigate the potential anti-dyskinetic efficacy of 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 (MPTP) 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 does employed in the study, we determined plasma, cerebrospinal fluid (CSF) and brain levels of L-745,870. Co-administration of L-745,870 (1 mg/kg) and L-DOPA significantly reduced the severity of dyskinesia, by up to 59%, in comparison to L-DOPA alone (P<0.01). L-745,870 had no effect on duration of anti-parkinsonian benefit, ON-time (P>0.05). However, L-745,870 (1 mg/kg) significantly increased duration of ON-time without disabling dyskinesia (+204%, P<0.001) and decreased duration of ON-time with disabling dyskinesia when compared to 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 to 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. Importantly, 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.
- Received April 16, 2012.
- Revision received May 21, 2012.
- Accepted May 21, 2012.
- The American Society for Pharmacology and Experimental Therapeutics