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Identification of Pyrrolidine‐3‐acetic Acid Derived Oximes as Potent Inhibitors of γ‐Aminobutyric Acid Transporter 1 through Library Screening with MS Binding Assays
ChemMedChem ( IF 3.4 ) Pub Date : 2018-11-28 , DOI: 10.1002/cmdc.201800556
Simone K. Huber 1 , Georg Höfner 1 , Klaus T. Wanner 1
Affiliation  

In this study, pyrrolidine‐3‐acetic acid derived oxime libraries were applied to the concept of library screening by MS Binding Assays, as a powerful technique to reveal new potent murine γ‐aminobutyric acid transporter subtype (mGAT1) inhibitors. Library generation was accomplished by condensation of an excess of pyrrolidine‐3‐acetic acid bearing a hydroxylamine unit with various libraries, each composed of eight different aldehydes. The oxime libraries have been screened by means of competitive MS Binding Assays and, as a consequence, the most active libraries were further investigated through deconvolution experiments to identify single oximes responsible for the observed activity on the target mGAT1. All identified hits were finally resynthesized to characterize them with respect to their binding affinities, and a set of new potent inhibitors with the pyrrolidine‐3‐acetic acid motif were found, of which the most potent oxime, possessing a 2′,4′‐dichlorobiphenyl residue, displayed a binding affinity in the low nanomolar range (pKi=7.87±0.01).

中文翻译:

通过MS结合试验筛选文库,鉴定出吡咯烷-3-乙酸衍生的肟作为γ-氨基丁酸转运蛋白1的强抑制剂

在这项研究中,将吡咯烷-3-乙酸衍生的肟文库应用于通过MS结合分析进行文库筛选的概念,这是揭示新型有效的鼠类γ-氨基丁酸转运蛋白亚型(mGAT1)抑制剂的强大技术。文库的生成是通过将带有羟胺单元的过量吡咯烷-3-乙酸与各种文库缩合来完成的,每个文库由八个不同的醛组成。肟文库已通过竞争性MS结合测定法进行了筛选,因此,通过解卷积实验进一步研究了活性最高的文库,以鉴定负责观察到的对目标mGAT1活性的单一肟。最终,所有识别出的匹配都经过重新合成,以根据它们的结合亲和力来表征它们,K i = 7.87±0.01)。
更新日期:2018-11-28
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