Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries
Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries
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DOI：
10.1021/acs.jmedchem.8b01602
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发表时间：
2018-11-22
影响因子：
7.3
通讯作者：
Wanner, Klaus T.
中科院分区：
文献类型：
--
作者：
Hauke, Tobias J.;Wein, Thomas;Wanner, Klaus T.
为寻找新型GABA转运蛋白GAT1的抑制剂，本研究以新的N-胡椒酸为核心结构，在5-位取代普通的1-位，筛选出动态组合文库。所生成的假静态分子Hydrazone文库总共包含近900个化合物，并通过基于竞争质谱学(MS)的结合分析对它们与GAT1的结合亲和力进行了筛选。在结合和吸收实验中，具有最高亲和力(顺式RAC-16gf含有5-(1-萘基)呋喃-2-基和四原子间隔基的RAC-16gf是最有效的)的特征表明，在GAT1上存在变构相互作用，这在任何其他的吡啶杂环酸衍生物中都没有报道。因此，本文所介绍的5-取代新胡椒酸衍生物可以作为研究GAT1介导的变构调控的GABA转运的有价值的工具，并进一步成为一类新的GAT1抑制剂的起点。
This study describes the screening of dynamic combinatorial libraries based on nipecotic acid as core structure with substituents attached to the 5-instead of the common 1-position for the search of novel inhibitors of the GABA transporter GAT1. The generated pseudostatic hydrazone libraries included a total of nearly 900 compounds and were screened for their binding affinities toward GAT1 in competitive mass spectrometry (MS) based Binding Assays. Characterization of the hydrazones with the highest affinities (with cis-configured rac-16gf bearing a 5-(1-naphthyl)furan-2-yl residue and a four atom spacer being the most potent) in binding and uptake experiments revealed an allosteric interaction at GAT1, which was not reported for any other nipecotic acid derivative up to now. Therefore, the herein introduced 5-substituted nipecotic acid derivatives could serve as valuable tools for investigations of allosterically modulated GABA transport mediated by GAT1 and furthermore as starting point for a new class of GAT1 inhibitors.