NOVEL 4-(ARYLOXY)TETRAHYDROPYRIDINE ANALOGS OF MPTP AS MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B SUBSTRATES
NOVEL 4-(ARYLOXY)TETRAHYDROPYRIDINE ANALOGS OF MPTP AS MONOAMINE-OXIDASE-A AND MONOAMINE-OXIDASE-B SUBSTRATES
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DOI：
10.1021/jm00033a012
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发表时间：
1994-04-01
影响因子：
7.3
通讯作者：
CASTAGNOLI, N
中科院分区：
文献类型：
--
作者：
KALGUTKAR, AS;CASTAGNOLI, K;CASTAGNOLI, N
与神经毒素MPTP相关的几种4-（芳基甲基）-1-甲基-1，2，3，6-四氢吡啶衍生物具有非常好的单胺氧化酶（MAO）底物性质，这促使研究评估在C-4处具有杂原子连接基团的四氢吡啶衍生物的相应性质。发现由4-（芳氧基）四氢吡啶类似物的这些MAO-A和MAO-B催化氧化产生的预期二氢吡啶代谢物会发生快速水解裂解，产生相应的芳烃醇和1-甲基-2，3-二氢-4-吡啶酮，这是一种可以通过分光光度法监测的物质。我们利用这一反应序列，用各种4-（芳氧基）-1-甲基-1，2，3，6-四氢吡啶衍生物探测牛肝MAO-B和人胎盘MAO-A的活性位点。结果进行了讨论，最近发表的报告描述的MAO-A与MAO-B的选择性的各种4-（芳甲基）四氢吡啶衍生物的关系。
The exceptionally good monoamine oxidase (MAO) substrate properties of several 4-(arylmethyl)-1-methyl-1,2,3,6-tetrahydropyridine derivatives related to the neurotoxin MPTP have prompted studies to evaluate the corresponding properties of tetrahydropyridine derivatives bearing heteroatom-linked groups at C-4. The expected dihydropyridinium metabolites generated from these MAO-A- and MAO-B-catalyzed oxidations of the 4-(aryloxy)tetrahydropyridine analogs were found to undergo rapid hydrolytic cleavage to yield the corresponding arenol and 1-methyl-2,3-dihydro-4-pyridone, a species that could be monitored spectrophotometrically. We have exploited this reaction sequence to probe the active sites of beef liver MAO-B and human placental MAO-A with a variety of 4-(aryloxy)-1-methyl-1,2,3,6-tetrahydropyridine derivatives. The results are discussed in relationship to recently published reports describing the MAO-A vs MAO-B selectivity of various 4-(arylmethyl)tetrahydropyridine derivatives.