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

用于治疗帕金森病的 NMDA-R2B 拮抗剂

• 批准号: 7958259
• 负责人: STELLA PAPPA
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958259
• 关键词: Animal Model; Antiparkinson Agents; Basal Ganglia; Behavior; Biological Availability; Brain; Cardiotoxicity; Characteristics; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Corpus striatum structure; Evaluation; Funding; Generations; Gold; Grant; Half-Life; Institution; Monkeys; Motor; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Parkinson Disease; Parkinsonian Disorders; Penetration; Potassium Channel; Primates; Property; Research; Research Personnel; Resources; Source; Specificity; Structural Chemistry; Symptoms; Testing; Toxic effect; United States National Institutes of Health; interest; novel

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本项目的目的是评估NR 2B-10076和NR 2B-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NR 2B选择性拮抗剂，具有高效力，良好的脑渗透性和延长的半衰期，从未被测试用于帕金森病。 运动效应的特异性和NMDA拮抗剂的较低毒性通常与NR 2B阻断剂一起寻求，因为含有NR 2B的NMDA受体在整个纹状体和基底神经节中大量表达。 其他选择性NR 2B阻断剂在动物模型中显示出抗帕金森病作用，但未能证明临床试验的安全性或有效性。 上一代NR 2B拮抗剂CP 101，606在灵长类动物中表现出明显的抗帕金森病作用，但具有严重的心脏毒性和较差的生物利用度。 对新化合物的特别关注源于它们的性质，其结合了对NR 2B的高选择性和效力以及缺乏这类NMDA拮抗剂的心脏毒性（hERG钾通道阻断）特征。NR 2B-10076和NR 2B-10068具有独特的结构化学，可提供有利的总体特征。 MPTP治疗的猴子，帕金森氏病的金标准动物模型的使用，允许NR 2B阻滞剂对帕金森氏症运动症状的具体影响进行全面评估。