QUANTITATIVE STRUCTURE METABOLISM RELATIONSHIP ANALYSES OF MAO-MEDIATED TOXICATION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE AND ANALOGS

被引:46
作者
ALTOMARE, C
CARRUPT, PA
GAILLARD, P
ELTAYAR, N
TESTA, B
CAROTTI, A
机构
[1] UNIV LAUSANNE,INST CHIM THERAPEUT,BEP,CH-1015 LAUSANNE,SWITZERLAND
[2] UNIV BARI,DIPARTIMENTO FARMACOCHIM,I-70125 BARI,ITALY
关键词
D O I
10.1021/tx00027a008
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The 1-octanol/water partition coefficients of a number of toxic and nontoxic analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were determined using centrifugal partition chromatography (CPC), a novel and effective technique for measuring lipophilicity, and found to be highly correlated with values calculated by a fragmental method. Some conformational properties of these compounds were also assessed by molecular mechanics calculations and H-1-NMR spectroscopy. A quantitative structure-metabolism relationship (QSMR) study of MPTP and analogues based on literature data was undertaken in order to determine the key features eliciting MAO-A and MAO-B reactivity and selectivity and influencing toxication. Multiple regression analysis (MRA) and comparative molecular field analysis (CoMFA) showed that MAO-B activity is nonlinearly (parabolically or bilinearly) correlated to the lipophilicity of MPTP analogues and influenced negatively by steric effects exerted by bulky substituents in the ortho position. With regard to MAO-A activity, while lipophilicity was shown to play no relevant role, electrostatic and steric fields led to a 3D-QSAR model with an acceptable predictive value (cross-validated r2 = 0.571). The results of this study bring evidence at a quantitative level that the MAO-B and MAO-A catalytic sites differ in their hydrophobic, steric, and stereoelectronic requirements.
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页码:366 / 375
页数:10
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