1,5-Disubstituted and 5-monosubstituted aminomethyltetrazole derivatives derived from glycine were synthesized employing a TMSN(3)-modified variant of the Ugi reaction as a key step. All compounds were evaluated regarding their inhibitory potency and subtype selectivity at the four murine GABA transporter subtypes mGAT1-mGAT4. Though none of the 5-monosubstituted tetrazoles turned out to inhibit [(3)H]GABA uptake to a significant extent, the 1,5-disubstituted tetrazole derivatives displayed a distinct activity, especially at the GABA transport proteins mGAT2-mGAT4. Thus, a reasonable potent and selective inhibitor of mGAT3 was found. Additionally, two more compounds were identified as potent inhibitors of mGAT2. This is especially relevant, as up to date only few potent inhibitors of mGAT2 that do not affect mGAT1 are known.
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