Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys.

Abstract

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.

• Authors: A Hadj Tahar, N Bélanger, E Bangassoro, L Grégoire, P J Bédard
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 399 Issue 2-3 Pg. 183-6 (Jul 07 2000) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10884518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• JL 18
• Levodopa
• Benserazide
• Clozapine

Topics

• Analysis of Variance
• Animals
• Antiparkinson Agents (pharmacology)
• Behavior, Animal (drug effects)
• Benserazide (pharmacology)
• Clozapine (analogs & derivatives, pharmacology)
• Dose-Response Relationship, Drug
• Dyskinesia, Drug-Induced (prevention & control)
• Female
• Levodopa (pharmacology)
• Macaca fascicularis
• Motor Activity (drug effects)
• Parkinsonian Disorders (drug therapy, physiopathology)