Identification of the First Highly Subtype-Selective Inhibitor of Human GABA Transporter GAT3

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• 作者：Maria Damgaard ; Anas Al-Khawaja ; Stine B. Vogensen ; Andreas Jurik ; Maarten Sijm ; Maria E. K. Lie ; Mathias I. B忙k ; Emil Rosenthal ; Anders A. Jensen ; Gerhard F. Ecker ; Bente Fr酶lund ; Petrine Wellendorph ; Rasmus P. Clausen
• 刊名：ACS Chemical Neuroscience
• 出版年：2015
• 出版时间：September 16, 2015
• 年：2015
• 卷：6
• 期：9
• 页码：1591-1599
• 全文大小：555K
• ISSN：1948-7193

文摘

Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [³H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure鈥揳ctivity relationship (SAR) study led to the identification of hGAT3-selective inhibitors (i.e., compounds 20 and 34) that were superior to the reference hGAT3 inhibitor, (S)-SNAP-5114, in terms of potency (low micromolar IC₅₀ values) and selectivity (>30-fold selective for hGAT3 over hGAT1/hGAT2/hBGT1). Further pharmacological characterization of compound 20 (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.