Sulfur-substituted alpha-alkyl phenethylamines as selective and reversible MAO-A inhibitors: biological activities, CoMFA analysis, and active site modeling.
A series of phenethylamine derivatives with various ring substituents and with or without N-methyl and/or C-alpha methyl or ethyl groups was synthesized and assayed for their ability reversibly to inhibit monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds showed potent and selective MAO-A inhibitory activity (IC(50) in the submicromolar range) but none showed appreciable activity toward MAO-B. A three-dimensional quantitative structure-activity relationship study for MAO-A inhibition was performed on the series using comparative molecular field analysis (CoMFA). The resulting model gave a cross-validated q(2) of 0.72 and showed that in this series of compounds steric properties of the substituents were more important than electrostatic effects. Molecular modeling based on the recently published crystal structure of inhibitor-bound MAO-A provided detailed evidence for specific interactions of the ligands with the enzyme, supported by previous references and consistent with results from the CoMFA. On the basis of these results, structural determinants for selectivity of substituted amphetamines for MAO-A are discussed.
Gallardo-Godoy
Alejandra
A
Department of Chemistry, Faculty of Sciences, Universidad de Chile, Casilla 653, Santiago, Chile.
Fierro
Angélica
A
McLean
Thomas H
TH
Castillo
Mariano
M
Cassels
Bruce K
BK
Reyes-Parada
Miguel
M
Nichols
David E
DE
D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000648:ultrastructure; D003010:Clorgyline / Q000737:chemistry; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D003010:Clorgyline