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

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) 帕金森氏症。最近报道的研究发现，灵长类动物被注射了 剂量相对较小的这种药物会出现症状和 与这种疾病非常相似的组织学图像增加了这种可能性 这种药物产生的影响可能与引起 帕金森症。 为了调查NMPTP的行动，概述了以下程序 高放射性NMPTP及其衍生物的有机合成 基于文献中描述的合成。有无线电标记的 化合物，将被用在动物身上以确定摄取和 毒品的处置。将进行实验，以确定是否存在 放射性药物的细胞定位对应于 已知的帕金森症患者的组织。亚细胞分布 该药物的含量也将得到确定。 尽管NMPTP会产生帕金森样效应，但没有信息表明 是否真的是致癌剂，或者这些影响是由于 这种化合物的代谢物。因此，NMPTP的新陈代谢将 使用经典的生化技术进行研究，在这些技术中 将化合物与组织切片、匀浆和亚细胞孵育 对馏分和反应产物进行了分离和表征。 然后可以合成反应产物并对其进行生理测试 效果。 一旦NMPTP的整体代谢被阐明，我们应该 意识到一种或多种化合物可能积聚并有可能 有毒的。这些化合物将通过使用放射性前体来合成 以及它们与来自中央的细胞成分的相互作用 神经系统将会被决定。关于化学结构的知识 将有助于预测可能的行动机制。合成纤维的使用 放射性标记化合物应该提供一种方法来揭示 这些化合物发挥其毒性作用的机制。

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.