Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand 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 D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 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.
Hadj Tahar
A
A
Neuroscience Research Unit (RC-9800), CHUL, Laval University Research Center, 2705 Boul. Laurier, G1V 4G2, Ste.-Foy, Quebec, Canada.
Ekesbo
A
A
Grégoire
L
L
Bangassoro
E
E
Svensson
K A
KA
Tedroff
J
J
Bédard
P J
PJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology; D001545:Benserazide / Q000008:administration & dosage / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008252:Macaca fascicularis; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010880:Piperidines; D017448:Receptors, Dopamine D2; C109513:OSU 6162; D007980:Levodopa; D001545:Benserazide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine