A2AR/MGLUR5 ANTAGONIST COMBINATION ANTIPARKINSONIAN THERAPY IN MPTP MONKEYS

A2AR/MGLUR5 拮抗剂联合抗帕金森病治疗 MPTP 猴

• 批准号: 8357543
• 负责人: Yoland Smith
• 金额: $ 3.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357543
• 关键词: Adenosine A2A Receptor; Adverse effects; Affinity; Antiparkinson Agents; Basal Ganglia; Behavior; Behavioral; Biological Availability; Cell Nucleus; Dopamine; Drug Receptors; Funding; GRM5 gene; Gold; Grant; KW-6002; Measures; Modeling; Monitor; Monkeys; Motor; National Center for Research Resources; Nature; Neurotransmitters; Parkinson Disease; Parkinsonian Disorders; Pharmaceutical Preparations; Pharmacological Treatment; Primates; Principal Investigator; Publishing; Research; Research Infrastructure; Resources; Source; System; Testing; Time; United States National Institutes of Health; cost; metabotropic glutamate receptor 5; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Current pharmacological treatments for Parkinson's Disease (PD) act on the dopamine neurotransmitter system and cause debilitating motor side effects. This project seeks to study new potential antiparkinsonian drugs (and their mechanisms of action) that act on other neurotransmitter systems and are therefore not likely to cause motor side effects. Antagonists of metabotropic glutamate receptor 5 (mGluR5) and adenosine A2A receptor (A2AR) are the focus of this study. These drugs will be injected systemically or locally into various nuclei of the basal ganglia of MPTP-treated parkinsonian monkeys (the gold-standard model of PD), and their motor behavior will be monitored. These drugs will be administered both alone and together. We have found that when injected systemically, the mGluR5 antagonist MTEP provides a modest anti-akinetic benefit to MPTP-treated monkeys. After trying several different A2AR antagonists, we have been unable to measure any behavioral antiparkinsonian effect in our monkeys, whether the drugs were administered systemically or locally in the basal ganglia, either given alone or in combination with mGluR5 antagonist. We were unable to obtain the only A2AR drug published to have antiparkinsonian effects in monkeys at the time (KW-6002), due to the proprietary nature of the drug. Since then, one more A2AR drug (preladenant) has been published to have antiparkinsonian effects in monkeys. We have made arrangements to get some of this new compound, with better affinity/selectivity/bioavailability, for testing in our monkeys.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 帕金森氏病（PD）的当前药理治疗对多巴胺神经递质系统的作用，并导致运动副作用使人衰弱。 该项目旨在研究对其他神经递质系统起作用的新潜在的抗帕金森氏菌药物（及其作用机制），因此不太可能引起运动副作用。 代谢剂谷氨酸受体5（MGLUR5）和腺苷A2A受体（A2AR）的拮抗剂是这项研究的重点。 这些药物将被全身或局部注入MPTP处理的Parkinsonian猴子基底神经节的各种核（PD的金标准模型），并将监测它们的运动行为。这些药物将单独和一起服用。 我们发现，在系统地注射时，MGLUR5拮抗剂MTEP为MPTP处理的猴子提供了适度的抗种性益处。 在尝试了几个不同的A2AR拮抗剂之后，我们无法在猴子中测量任何行为反帕金森氏症的作用，无论这些药物是在基底神经节中全身或本地施用的，无论是单独或与MGLUR5拮抗剂结合使用。 由于该药物的专有性，我们无法获得唯一在当时（KW-6002）出版的A2AR药物（KW-6002）。 从那时起，另外一种A2AR药物（前）已出版，在猴子中具有反帕金森氏症的作用。 我们已经安排了一些新化合物，并具有更好的亲和力/选择性/生物利用度，以在我们的猴子中进行测试。