Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Studies on 4-benzyl-1-methyl-1,2,3,6-tetrahydropyridine, a nonneurotoxic analogue of the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
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4-苄基-1-甲基-1,2,3,6-四氢吡啶的研究，帕金森病诱导剂 1-甲基-4-苯基-1,2,3,6-四氢吡啶的非神经毒性类似物。
DOI：
10.1021/tx00014a008
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发表时间：
1990
影响因子：
4.1
通讯作者：
CastagnoliJr,N
中科院分区：
文献类型：
--
作者：
Naiman,N;Rollema,H;Johnson,E;CastagnoliJr,N
先前的报道表明，4-苄基-1-甲基-1，2，3，6-四氢吡啶（BMTP），即帕金森病诱导性神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的苄基类似物，即使以比引起新纹状体多巴胺85%消耗所需的MPTP剂量大10倍的剂量给药，在C-57黑小鼠中也没有神经毒性。然而，在大鼠中用相应的4-苄基-1-甲基吡啶离子BMP+进行纹状体内微透析60分钟，引起的神经末梢破坏与用1-甲基-4-苯基吡啶离子MPP+灌注15分钟后观察到的类似，MPP+是由MPTP衍生的单胺氧化酶B（MAO-B）产生的代谢物。借助于纯化的牛肝MAO-B和合成标准品，我们观察到BMTP有效和定量地转化为相应的2，3-二氢吡啶鎓中间体BMDP+，其经历进一步但不完全的氧化为BMP-1。这些MPTP类型的属性指向体内效应，如药代动力学参数和/或替代代谢途径，以解释BMTP缺乏神经毒性。
Previous reports indicate that 4-benzyl-l-methyl-l, 2, 3, 6-tetrahydropyridine (BMTP), the benzyl analogue of the Parkinsonian inducing neurotoxinl-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP), is not neurotoxic in the C-57 black mouse even when administered at a dose 10 times greater than the dose of MPTP required to cause an 85% depletion of neostriatal dopamine. Intrastriatal microdialysis in the rat with the corresponding 4-benzyl-l-methylpyridinium ion BMP"* 1" for 60 min, however, causes nerve terminal destruction similar to that observed following a 15-min perfusion with the l-methyl-4-phenylpyridinium ion MPP+, the monoamine oxidase B (MAO-B) generated metabolite derived from MPTP. With the aid of purified beef liver MAO-B and synthetic standards, we observed the efficient and quantitative conversion of BMTP to the corresponding 2, 3-dihydropyridinium intermediate BMDP+, which underwent further, but incomplete, oxidation to BMP" 1". These MPTP-type properties point to in vivo effects, such as pharmacokinetic parameters and/or alternative metabolic pathways, to account forBMTP’s lack of neurotoxicity.