MOLECULAR-BASIS OF DISCREPANCIES IN NEUROTOXIC PROPERTIES AMONG 1-METHYL-4-ARYL-1,2,3,6-TETRAHYDROPYRIDINES

被引:2
|
作者
BACHURIN, SO
SABLIN, SO
LERMONTOVA, NN
SOLYAKOV, LS
DUBOVA, LG
TKACHENKO, SE
机构
[1] Institute of Physiologically Active Substances, Russian Academy of Sciences, Moscow Region, 142432, Chernogolovka
关键词
NEUROTOXICITY OF MPTP AND ITS 4-TOLYL HOMOLOGS; MONOAMINE OXIDASE (MAO) CATALYSIS OF BIOCONVERSION OF MPTP AND ITS HOMOLOGS; MECHANISM OF AUTOINACTIVATION OF MAO DURING MPTP OXIDATION; AFFINITY OF 1-METHYL-4-PHENYL-PYRIDINIUM AND ITS TOLYL HOMOLOGS TOWARD DOPAMINE UPTAKE SYSTEM; STRUCTURE-ACTIVITY RELATIONSHIPS IN THE NUMBER OF MPTP HOMOLOGS;
D O I
10.1007/BF03160009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The relationship between structural specificity of the main stages of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action and the display of parkinsonogenic properties among homologous structures in a number of 4-tolyl derivatives of MPTP has been studied. All the compounds are better substrates for monoamine oxidase (MAO) than MPTP. MAO is inactivated during the reaction according to a mechanism of irreversible inhibition by 2,3-dihydropyridinium metabolite. All the tolyl derivatives are stronger inhibitors of MAO than 1-methyl-2,3-dihydropyridinium (MPDP). A significant contribution of enzyme inhibition to the catalytic conversion of the substrate leads to the fact that substrates having equal (para isomer) or even higher (meta isomer) values of catalytic parameters are oxidized by MAO to a lesser extent than MPTP. It has been found that all 4-arylpyridiniums (final products of MATP bioconversion) competitively and reversibly inhibit [C-14]dopamine (DA) uptake in mouse brain synaptosomes. Affinity toward DA transporter characterized by K(I) (muM) is 0.37+/-0.04, 0.7+/-0.1, 2.0+/-0.15, 2.0+/-0.35 for MPP, and its o-, m-, and p-tolyl derivatives, respectively. Joint calculation of specificity factors for the processes discussed define the following rank order for the bio-delivery of MATP's metabolic produces into DA nerve terminals: o-tolyl>MPTP>>m-tolyl>p-tolyl. The regularity revealed is in good agreement with the observed relative potency of these compounds to cause dopaminergic neurodegeneration.
引用
收藏
页码:189 / 200
页数:12
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