Synthesis and biological evaluation of α- and β-hydroxy substituted amino acid derivatives as potential mGAT1–4 inhibitors

Abstract

In this study, we report the synthesis and biological evaluation of a variety of α- and β-hydroxy substituted amino acid derivatives as potential amino acid subunits in inhibitors of GABA uptake transporters (GATs). In order to ensure that the test compounds adopt a binding pose similar to that presumed for related larger GAT inhibitors, lipophilic residues were introduced either at the amino nitrogen atom or at the alcohol function. Several of the synthesized compounds were found to exhibit similar inhibitory activity at the GAT subtypes mGAT2, mGAT3, and mGAT4, respectively, as compared with the reference N-butylnipecotic acid. Hence, these compounds might serve as starting point for future developments of more complex GAT inhibitors.