jm0493109_si_001.pdf (37.42 kB)
Sulfur-Substituted α-Alkyl Phenethylamines as Selective and Reversible MAO-A Inhibitors: Biological Activities, CoMFA Analysis, and Active Site Modeling
journal contribution
posted on 2005-04-07, 00:00 authored by Alejandra Gallardo-Godoy, Angélica Fierro, Thomas H. McLean, Mariano Castillo, Bruce K. Cassels, Miguel Reyes-Parada, David E. NicholsA series of phenethylamine derivatives with various ring substituents and with or without
N-methyl and/or C-α 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 (IC50 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 q2 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.