Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Studies on the 1-methyl-4-phenyl-2,3-dihydropyridinium species 2,3-MPDP+, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
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1-甲基-4-苯基-2,3-二氢吡啶鎓类 2,3-MPDP 的研究，黑质纹状体毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶的单胺氧化酶催化氧化产物
DOI：
10.1021/jm00148a010
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发表时间：
1985
影响因子：
7.3
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
--
作者：
Peterson,LA;Caldera,PS;Trevor,A;Chiba,K;CastagnoliJr,N
黑质纹状体毒素L-甲基-4-苯基-L，2，3，6-四氢吡啶被脑单胺氧化酶生物转化为一种不稳定的二氢吡啶中间体，该中间体与氰离子反应生成a-氰基-四氢吡啶加合物，在无氰离子存在下发生歧化反应生成L-甲基-4-苯基吡啶物种MPP+和MPTP。通过与合成标准化合物的高效液相色谱保留时间、二极管阵列紫外光谱和化学离子质谱学特征的比较，我们提出1-甲基-4-苯基-2，3-二氢吡啶物种2，3-mpdp+和6-氰基-L-甲基-4-苯基-L，2，3，6-四氢吡啶分别作为二氢吡啶代谢物和氰基加合物的初步结构归属。本文的结果证实了第一个指认，并证实，虽然所提出的6-氰基加合物最初是形成的，但从MPTP和氰化钠的线粒体孵育混合物中分离出来的产物实际上是2-氰基-L-甲基-4-苯基-L，2，3，6-四氢吡啶。在此基础上，我们对氰基加合物的歧化反应和重排反应进行了合理的机理解释。这些结果表明，MAO催化的MPTP的生物激活导致了各种对黑质纹状体细胞具有潜在细胞毒性的反应分子的形成。
The nigrostriatal toxin l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP) is biotransformed by brain monoamine oxidase (MAO) to an unstable dihydropyridinium intermediate that reacts with cyanide ion to form an a-cyano-tetrahydropyridine adductand, in the absence of cyanide ion, undergoes disproportionation to the l-methyl-4-phenylpyridinium species MPP+ and MPTP. Comparison of the HPLC retention times, diode array UV, and chemical ion mass spectral characteristics of these products with those of synthetic standards led us to propose the 1-methyl-4-phenyl-2, 3-dihydropyridinium species 2, 3-MPDP+ and 6-cyano-l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine as tentative structure assignments for the dihydropyridinium metabolite and the cyano adduct, respectively. Results presented in this paper confirm the first assignment and establish that, although theproposed 6-cyano adduct is initially formed, the product that was isolated from the mitochondrial incubation mixtures of MPTP and sodium cyanide actually is the isomeric 2-cyano-l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine. On the basis of the selective incorporation of deuterium into these products, we provide rational mechanistic interpretations of the disproportionation reaction and the rearrangement of the cyano adducts. These results establish that the MAO-catalyzed bioactivation of MPTP leads tothe formation of a variety of reactive molecules that are potentially cytotoxic to nigrostriatal cells.