Effects of acute and repeated treatment with a novel dopamine D-2 receptorligand on L-DOPA-induced dyskinesias in MPTP monkeys

(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 recept or antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias i n a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2, 3,6-t etrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinson ian 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 co ntrol. L-DOPA/benserazide increased locomotion and improved parkinsonism bu t also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/be nserazide produced a significant reduction in L-DOPA-induced dyskinesias. T his improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duratio n 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 th is effect was observed. Our data suggests that (-)-OSU6162 could be of sign ificant clinical Value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients. (C) 2001 Elsevier Science B.V. All r ights reserved.