Quantitative structure-metabolism relationship analyses of MAO-mediated toxication of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analogues.
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 1H-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.
Altomare
C
C
Institut de Chimie Thérapeutique, Ecole de Pharmacie, Université de Lausanne, Switzerland.
Carrupt
P A
PA
Gaillard
P
P
el Tayar
N
N
Testa
B
B
Carotti
A
A
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000378:metabolism; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D020267:MPTP Poisoning; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008995:Monoamine Oxidase / Q000378:metabolism*; D012044:Regression Analysis; D013329:Structure-Activity Relationship
C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase