Sulfur-Substituted α-Alkyl Phenethylamines as Selective and Reversible MAO-A Inhibitors:  Biological Activities, CoMFA Analysis, and Active Site Modeling Alejandra Gallardo-Godoy Angélica Fierro Thomas H. McLean Mariano Castillo Bruce K. Cassels Miguel Reyes-Parada David E. Nichols 10.1021/jm0493109.s001 https://acs.figshare.com/articles/journal_contribution/Sulfur_Substituted_Alkyl_Phenethylamines_as_Selective_and_Reversible_MAO_A_Inhibitors_Biological_Activities_CoMFA_Analysis_and_Active_Site_Modeling/3292252 A series of phenethylamine derivatives with various ring substituents and with or without <i>N-</i>methyl and/or C-<i>α</i> 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<sub>50</sub> 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 <i>q</i><sup>2</sup> 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. 2005-04-07 00:00:00 Molecular modeling ability reversibly α methyl submicromolar range series Active Site Modeling ring substituents ethyl groups phenethylamine derivatives compounds steric properties Several compounds monoamine oxidase crystal structure IC 50 CoMFA Analysis field analysis monoamine oxidase B