SYNTHESIS OF NOVEL MPTP ANALOGS AS POTENTIAL MONOAMINE OXIDASE-B (MAO-B) INHIBITORS
SYNTHESIS OF NOVEL MPTP ANALOGS AS POTENTIAL MONOAMINE OXIDASE-B (MAO-B) INHIBITORS
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DOI：
10.1021/jm00100a023
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发表时间：
1992-10-30
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, N
黑纹状体毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是黄酶单胺氧化酶B （MAO-B）的优良底物和弱灭活剂。为了开发新的基于机制的MAO-B灭活剂，我们合成了MPTP的类似物，这些类似物在N或C(4)位置上具有多种官能团，并研究了它们与从牛肝中分离的纯化MAO-B制剂的相互作用。所选择的取代基包括烯丙基、丙炔基、乙烯基、乙基和环丁基，即被认为是酶生成的亲电中间体或自由基中间体的潜在来源，这些中间体可能烷基化并使酶失活。虽然一些C(4)取代的化合物被证明是良好的底物，但没有一种化合物显示出明显的酶抑制剂性能。在n取代的MPTP系列中，只有4-苯基-1-丙炔类似物是良好的抑制剂。该化合物对MAO-B的抑制作用具有时间和浓度依赖性，这与目前单胺氧化酶的失活途径和催化机制一致。这些研究结果为MAO-B活性位点的立体特征提供了额外的见解，并预测四氢吡啶环的C(4)取代基所在的区域缺乏反应性亲核基团。
The nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an excellent substrate and a weak inactivator of the flavoenzyme monoamine oxidase B (MAO-B). In an attempt to develop novel mechanism-based inactivators of MAO-B, we have synthesized analogs of MPTP bearing a variety of functional groups at either the N or the C (4) position and have examined their interactions with a purified MAO-B preparation isolated from beef liver. The substituents selected include allyl, propargyl, ethenyl, ethynyl, and cyclobutyl, that is, functionalities which were considered potential sources of enzyme generated electrophilic or radical intermediates that might alkylate and inactivate the enzyme. None of the C(4)-substituted compounds displayed significant enzyme inhibitor properties although some proved to be good substrates. In the N-substituted MPTP series only the 4-phenyl-1-propargyl analog was a good inhibitor. The time- and concentration-dependent inhibition of MAO-B displayed by this compound is consistent with a mechanism-based inactivation pathway and the catalytic mechanism currently held for monoamine oxidases. The results of these studies provide additional insights into the steric features of the active site of MAO-B and predict that the area in which the C (4) substituent of the tetrahydropyridine ring resides lacks a reactive nucleophilic group.