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