ACTION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE

1-甲基-4-苯基-1,2,3,6-四氢吡啶的作用

• 批准号: 3403200
• 负责人: ROY W KEENAN
• 金额: $ 7.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1987-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3403200
• 关键词: Parkinson's disease; chromatography; cytotoxicity; density gradient ultracentrifugation; drug adverse effect; drug design /synthesis /production; drug metabolism; neurochemistry; neurologic manifestations; neurotoxins; radioassay; sign /symptom; tyrosine 3 monooxygenase

The long-term objective of this research is to relate the action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) to the cause of Parkinson's disease. The recently reported finding that primates injected with relatively small doses of this drug developed symptoms and a histological picture closely resembling this disease raises the possibility that the effects produced by this drug might be the same as those causing Parkinsonism. In order to investigate the action of NMPTP, procedures are outlined for the organic synthesis of highly radioactive NMPTP and related derivatives based on the syntheses described in the literature. The radiolabeled compounds, will be administered to animals to determine the uptake and disposal of the drug. Experiments will be conducted to see if there is a cellular localization of the radioactive drug that corresponds to the tissues known to be affected in Parkinsonism. The subcellular distribution of the drug will also be determined. Although NMPTP produces parkinson-like effects there is no information as to whether it is actually the causitive agent or these effects are due to a metabolite of this compound. For this reason the metabolism of NMPTP will be studied using classical biochemical techniques in which the radioactive compound is incubated with tissue slices, homogenates, and subcellular fractions and the reaction products are isolated and characterized. Reaction products can then be synthesized and tested for the physiological effects. Once the overall metabolism of NMPTP has been elucidated, we should be aware of one or more compounds that may accumulate and are potentially toxic. These compounds will by synthesized using radioactive precursors and their interaction with cellular components derived from the central nervous system will be determined. A knowledge of the chemical structures will aid in predicting possible mechanisms of action. The use of synthetic radiolabeled compounds should provide an approach to uncovering the mechanism by which these compounds exert their toxic action.

这项研究的长期目标是将 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (NMPTP) 导致 帕金森病。 最近报道的发现灵长类动物注射 使用相对较小剂量的这种药物会出现症状，并且 组织学图片与这种疾病非常相似，提出了这种可能性 该药物产生的作用可能与引起的作用相同 帕金森症。 为了调查 NMPTP 的作用，概述了以下程序： 高放射性NMPTP及相关衍生物的有机合成 基于文献中描述的合成。 放射性标记的 化合物，将被给予动物以确定吸收和 药物的处置。 将进行实验，看看是否存在 对应于放射性药物的细胞定位 已知受帕金森病影响的组织。 亚细胞分布 药物的含量也将被确定。 尽管 NMPTP 会产生帕金森样效应，但没有任何信息表明 是否确实是致病因素，或者这些影响是由于 该化合物的代谢物。 因此 NMPTP 的代谢会 使用经典生化技术进行研究，其中放射性 将化合物与组织切片、匀浆和亚细胞一起孵育 分离并表征馏分和反应产物。 然后可以合成反应产物并测试其生理学 影响。 一旦阐明了 NMPTP 的整体代谢，我们就应该 意识到一种或多种可能积累并有可能发生的化合物 有毒的。 这些化合物将使用放射性前体合成 以及它们与来自中枢的细胞成分的相互作用 神经系统将被确定。 化学结构知识 将有助于预测可能的作用机制。 合成的使用 放射性标记化合物应该提供一种方法来揭示 这些化合物发挥毒性作用的机制。