Novel parent structures for inhibitors of the murine GABA transporters mGAT3 and mGAT4

Searching for potent and subtype selective parent structures of the murine γ-aminobutyric acid (GABA) transporter subtypes mGAT3 and mGAT4 a series of amino acids was characterised in a uniform [3H]GABA uptake test system based on transiently expressed mGAT1-4. From several potent inhibitors showing IC50 values at mGAT3 and mGAT4 in the low μM range cis-4-aminocrotonic acid and (RS)-2,3-diaminopropionic acid turned out to be most subtype selective for these transporters. With (RS)-isoserine - a compound unknown as GAT inhibitor until now - one of the most potent amino acids selectively inhibiting mGAT3 and mGAT4 was found. Furthermore, (2-amino-1,3-thiazol-4-yl)acetic acid was identified as the first parent structure exhibiting a clear, though still moderate, selective inhibition of GABA uptake at mGAT3.