Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on l-DOPA-induced dyskinesias in MPTP monkeys

Abstract ( S )-(−)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((−)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D 2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D 2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (−)-OSU6162, on l -3,4-dihydroxyphenylalanine ( l -DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to l -DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with l -DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; l -DOPA/benserazide) alone or in combination with (−)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. l -DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (−)-OSU6162 with l -DOPA/benserazide produced a significant reduction in l -DOPA-induced dyskinesias. This improvement in l -DOPA-induced dyskinesias occurred mainly at the onset of the l -DOPA/benserazide effect as reflected by an increase in the duration of the “ON” state without dyskinesias up to 3.4 fold after (−)-OSU6162 co-administration as compared to l -DOPA/benserazide alone. The anti-dyskinetic effect of (−)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (−)-OSU6162 could be of significant clinical value to reduce l -DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.