NMDA-R2B ANTAGONISTS FOR THE THERAPY OF PARKINSON?S DISEASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本项目的目的是评价NR2B-10076和NR2B-10068对MPTP帕金森病猴运动行为的影响。这些化合物是两种新型的NR2B选择性拮抗剂，具有高效、良好的脑渗透性和延长的半衰期，从未被测试过用于帕金森氏病。NR2B阻滞剂通常寻求运动效应的特异性和毒性较低的NMDA拮抗剂，因为含有NR2B的NR2B受体在纹状体和基底节大量表达。其他选择性NR2B阻滞剂已经在动物模型中显示出抗帕金森症的作用，但在临床试验中未能证明是安全或有效的。上一代NR2B拮抗剂CP101,606在灵长类动物中有明显的抗帕金森病作用，但具有严重的心脏毒性和较低的生物利用度。 对新化合物的特别兴趣来自于它们的特性，它们结合了对NR2B的高选择性和有效性，以及这类NMDA拮抗剂的无心脏毒性(HERG钾通道阻断)的特点。NR2B-10076和NR2B-10068具有独特的结构化学，使其具有有利的整体轮廓。使用MPTP治疗的猴子，这是帕金森氏病的黄金动物模型，允许彻底评估NR2B阻滞剂对帕金森病运动症状的具体影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The aim of this project is to evaluate the effects of NR2B-10076 and NR2B-10068 on motor behavior of MPTP parkinsonian monkeys. These compounds are two novel NR2B-selective antagonists of high potency, good brain penetration and prolonged half-life that have never been tested for Parkinson's disease. Specificity of motor effects and lower toxicity of NMDA antagonists are usually sought with the NR2B blockers because NR2B containing NMDA receptors are expressed abundantly throughout the striatum and basal ganglia. Other selective NR2B blockers have shown antiparkinsonian effects in animal models but failed to prove safe or efficacious for clinical trials. CP101,606, a previous generation NR2B antagonist showed clear antiparkinsonian effects in primates, however, it possessed important cardiac toxicity and poor bioavailability. The special interest in the new compounds derives from their properties combining high selectivity and potency for NR2B with the lack of cardiac toxicity (hERG potassium channel blockade) characteristic of this class of NMDA antagonists. NR2B-10076 and NR2B-10068 have a unique structural chemistry that confers an advantageous overall profile. The use of MPTP-treated monkeys, the gold-standard animal model of Parkinsons's disease, permits a thorough evaluation of specific effects of NR2B blockers on parkinsonian motor symptoms.