Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: Insights from molecular modeling studies

Abstract—Four enantiomerically pure (S)-4-alkylthioamphetamine derivatives were evaluated as monoamine oxidase (MAO) inhibitors using the human and rat isoforms of the enzyme. Molecular dockings were performed in order to gain insights regarding the binding mode of these inhibitors. All compounds were potent and selective MAO-A inhibitors although different rank orders of potencies were observed against the enzymes from different species. This behavior can be rationalized on the basis of different binding modes to each enzyme, as determined in silico. These findings further support the concept that MAO inhibitory activity of novel compounds, determined with enzymes from diverse mammalian species, should be considered with caution if human MAO is the final target to be addressed.This work was partially funded by FONDECYT Grant 1060199 and DICYT Grant 020591RPRP. D.E.E. acknowledges research support from the National Institutes of Health (GM29433). The compounds described were synthesized by MOO during a stay in Prof. E. Breitmaier’s laboratory at the University of Bonn as the recipient of a DAAD grant. We also thank Dr. Juan Guerrero for his assistance in the NMR spectroscopy with the chiral shift reagent, Ms. Milagros Aldeco for the preparation of purified recombinant human MAO A and MAO B, and Drs. G. Zapata-Torres and C. Mascayano and Prof. M. C. Rezende for their contribution to the computational work. A.F. was the recipient of CONICYT and MECESUP scholarship