Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in 
parkinsonian patients. To test if the antidyskinetic effect of clozapine is 
related to antagonism at the dopamine D(4) receptor, we investigated the effect 
of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine 
(JL-18), a structural analog of clozapine which is more selective for this 
receptor. Four 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. 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 JL-18 (at the doses of 
0.1, 0.3, or 0.9 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 JL-18, at low doses (0.1, 0.3 
mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in 
L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The 
present results suggest that novel selective dopamine D(4) receptor antagonists 
may represent a useful tool to reduce L-Dopa-induced dyskinesias.