Vol. 290, Issue 3, 1034-1040, September 1999

Differing Effects of N-methyl-D-aspartate Receptor Subtype Selective Antagonists on Dyskinesias in Levodopa-Treated 1-Methyl-4-phenyl-tetrahydropyridine Monkeys¹

P. J. Blanchet², S. Konitsiotis³, E. R. Whittemore⁴, Z. L. Zhou⁴, R. M. Woodward⁴ and T. N. Chase³

Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phosphononorvaline (MDL 100,453), and a novel noncompetitive allosteric site antagonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were then correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocytes. MDL 100,453 (300 mg/kg s.c.) by itself increased global motor activity (p = .0005 versus vehicle) and administered 15 min after a low dose of levodopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-dependent potentiation of antiparkinsonian responses and also produced dyskinesias. Following injection of a fully effective dose of levodopa, MDL 100,453 (300 mg/kg s.c.) also produced a 25% increase in mean dyskinesia score (p = .04). In contrast, Co 101244 did not change motor activity by itself and only showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistical significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg/kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectively) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMDA glutamate-site antagonist, with ~5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K_b = 0.6 µM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed ~10,000-fold selectivity for the NR1A/NR2B (IC₅₀ = 0.026 µM) versus the other three subunit combinations tested. Taken together, the data suggest that the NR2 subunit selectivity profile of NMDA receptor antagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be useful agents in the treatment of Parkinson's disease.