Identification of the First Highly Subtype-Selective
Inhibitor of Human GABA Transporter GAT3
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Abstract
Screening a library of small-molecule
compounds using a cell line
expressing human GABA transporter 3 (hGAT3) in a [<sup>3</sup>H]GABA
uptake assay identified isatin derivatives as a new class of hGAT3
inhibitors. A subsequent structure–activity relationship (SAR)
study led to the identification of hGAT3-selective inhibitors (i.e.,
compounds <b>20</b> and <b>34</b>) that were superior
to the reference hGAT3 inhibitor, (<i>S</i>)-SNAP-5114,
in terms of potency (low micromolar IC<sub>50</sub> values) and selectivity
(>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further
pharmacological
characterization of compound <b>20</b> (5-(thiophen-2-yl)indoline-2,3-dione)
revealed a noncompetitive mode of inhibition at hGAT3. This suggests
that this compound class, which has no structural resemblance to GABA,
has a binding site different from the substrate, GABA. This was supported
by a molecular modeling study that suggested a unique binding site
that matched the observed selectivity, inhibition kinetics, and SAR
of the compound series. These compounds are the most potent GAT3 inhibitors
reported to date that provide selectivity for GAT3 over other GABA
transporter subtypes