Differing effects of N-methl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys

The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phospho nonorvaline (M DL 100,453), and a novel noncompetitive allosteric site anta gonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzl)piperidine (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phe nyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were t hen correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocy tes. 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 lev odopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-depend ent potentiation of antiparkinsonian responses and also produced dyskinesia s. 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 onl y showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistica l significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg /kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectiv ely) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMD A glutamate-site antagonist with similar to 5- to 10-fold selectivity for t he NR1A/NR2A subtype combination (K-b = 0.6 mu M) versus NR1A in combinatio n with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed similar to 10,000-fold selectivity for the NR1A/NR2B (IC50 = 0.026 mu M) versus the other three subunit combinations tested. Taken together, t he data suggest that the NR2 subunit selectivity profile of NMDA receptor a ntagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be us eful agents in the treatment of Parkinson's disease.