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.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目前帕金森病（PD）的药物治疗作用于多巴胺神经递质系统，并导致衰弱的运动副作用。 该项目旨在研究新的潜在抗帕金森病药物（及其作用机制），这些药物作用于其他神经递质系统，因此不太可能引起运动副作用。 代谢型谷氨酸受体5（mGluR 5）和腺苷A2 A受体（A2 AR）的拮抗剂是本研究的重点。 将这些药物全身或局部注射到MPTP治疗的帕金森病猴（PD的金标准模型）基底神经节的各个核团中，并监测它们的运动行为。这些药物将单独和联合给药。 我们已经发现，当全身注射时，mGluR 5拮抗剂MTEP为MPTP治疗的猴子提供适度的抗运动不能益处。 在尝试了几种不同的A2 AR拮抗剂后，我们无法在我们的猴子中测量任何行为抗帕金森病作用，无论药物是全身给药还是基底神经节局部给药，单独给药还是与mGluR 5拮抗剂联合给药。 由于该药物的专有性质，我们无法获得当时唯一发表的在猴中具有抗帕金森病作用的A2 AR药物（KW-6002）。 从那时起，又有一种A2 AR药物（preladenant）在猴子中具有抗帕金森病作用。 我们已经安排了一些这种新化合物，具有更好的亲和力/选择性/生物利用度，用于在我们的猴子中进行测试。