BIOACTIVATION OF TERT-ALLYLAMINES (MPTP) TO NEUROTOXINS

叔烯丙基胺1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP） 选择性破坏黑质纹状体含多巴胺的神经元 系统在人类和各种实验动物。 的机制 MPTP表达的神经毒性已经被证明涉及大脑 单胺氧化酶，其催化该化合物氧化成 相应的2，3-二氢吡啶鎓物质。 为了记录更多 充分的分子事件负责MPTP的毒性，我们建议， 进行单胺的化学和生化表征 氧化酶催化的MPTP氧化和选择的结构相关的 叔烯丙基胺 具体而言，我们建议研究（1）生物有机 该反应的机制，（2）体外代谢概况和动力学 提出的MPTP的MAO催化生物转化的参数 类似物和（3）这些类似物在小鼠中的神经毒性潜力 模型 这些研究的结果应该有助于确定那些 这种类型的微弧氧化基板所需的结构参数， 表征MAO催化MPTP氧化的贡献 导致MPTP诱导的生物事件的复杂性 黑质纹状体细胞的破坏。

The tertiary allylamine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys the dopamine containing neurons of the nigrostriatal system in humans and a variety of experimental animals. The mechanism by which MPTP expresses its neurotoxicity has been shown to involve brain monoamine oxidase which catalyzes the oxidation of this compound to the corresponding 2,3-dihydropyridinium species. In order to document more fully the molecular events responsible for MPTP's toxicity, we propose to undertake the chemical and biochemical characterization of the monoamine oxidase catalyzed oxidation of MPTP and selected structurally related tertiary allylamines. Specifically we propose to study (1) the bioorganic mechanism of this reaction, (2) the in vitro metabolic profiles and kinetic parameters of the MAO catalyzed biotransformation of the proposed MPTP analogs and (3) the neurotoxic potential of these analogs in the mouse model. The results of these studies should help to identify those structural parameters which are required for this type of MAO substrate and to characterize the contribution which the MAO catalyzed oxidation of MPTP makes to the complex of biological events responsible for the MPTP induced destruction of nigrostriatal cells.