Blanchet P J, Konitsiotis S, Whittemore E R, Zhou Z L, Woodward R M, Chase T N
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
J Pharmacol Exp Ther. 1999 Sep;290(3):1034-40.
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)piper idi ne (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 approximately 5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K(b) = 0.6 microM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed approximately 10,000-fold selectivity for the NR1A/NR2B (IC(50) = 0.026 microM) 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.
在六只经左旋多巴治疗的1-甲基-4-苯基-四氢吡啶损伤的帕金森病猴子中，评估了两种N-甲基-D-天冬氨酸（NMDA）受体拮抗剂的抗帕金森病和抗运动障碍特性，一种是竞争性拮抗剂（R）-4-氧代-5-膦酰基正缬氨酸（MDL 100,453），另一种是新型非竞争性变构位点拮抗剂4-羟基-N-[2-(4-羟基苯氧基)乙基]-4-(4-甲基苄基)哌啶（Co 101244/PD 174494）。然后将这两种药物单独以及与左旋多巴联合使用时对运动功能的影响，与NMDA亚型选择性以及对非洲爪蟾卵母细胞中表达的四种二聚体NMDA受体亚基组合的表观亲和力进行关联。MDL 100,453（300mg/kg皮下注射）单独使用时可增加整体运动活性（与赋形剂相比，p = 0.0005），在皮下注射低剂量左旋多巴/苄丝肼15分钟后给药，MDL 100,453（50、300mg/kg皮下注射）显示出抗帕金森病反应的剂量依赖性增强，并且还产生了运动障碍。注射完全有效剂量的左旋多巴后，MDL 100,453（300mg/kg皮下注射）还使平均运动障碍评分增加了25%（p = 0.04）。相比之下，Co 101244单独使用时不会改变运动活性，仅在与低剂量左旋多巴联合使用时显示出增强抗帕金森病反应的趋势，但未达到统计学显著性。然而，使用高剂量左旋多巴时，Co 101244（0.1、1mg/kg皮下注射）显示出抗运动障碍作用（分别降低67%和71%），同时保留了左旋多巴的运动益处。在体外，MDL 100,453是一种NMDA谷氨酸位点拮抗剂，对NR1A/NR2A亚型组合（K(b) = 0.6μM）的选择性比对与2B、2C或2D组合的NR1A高约5至10倍。相比之下，变构位点拮抗剂Co 101244对NR1A/NR2B（IC(50) = 0.026μM）的选择性比对测试的其他三种亚基组合高约10000倍。综上所述，数据表明NMDA受体拮抗剂的NR2亚基选择性谱在预测行为结果方面可能起重要作用，并提供了更多证据表明NR2B选择性NMDA受体拮抗剂可能是治疗帕金森病的有用药物。
