Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1
Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1
复制标题
设计和合成基于环丙烷的构象限制性 GABA 类似物作为甜菜碱/GABA 转运蛋白 1 的选择性抑制剂
DOI：
10.1016/j.bmcl.2018.08.031
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发表时间：
2018
影响因子：
2.7
通讯作者：
Shuto Satoshi
中科院分区：
文献类型：
--
作者：
Suemasa Akihiro;Watanabe Mizuki;Kobayashi Takaaki;Suzuki Hiroe;Fukuda Hayato;Minami Masabumi;Shuto Satoshi
我们先前设计并合成了一系列基于环丙烷的γ-氨基丁酸构象受限类似物。研究表明，对甜菜碱/GABA转运蛋白1(BGT1)亚型具有选择性活性的类似物的临界构象为反式构象，其中氨基和羧基是构型内的，环丙烷环和羧基是不同步排列的。在本研究中，我们设计并合成了环丙烷基GABA类似物，基于环丙烷邻位碳的立体化学原理，环丙酸菌株将其限制为反式构象。其构象经计算和核磁共振研究证实为同型，其药理评价表明，化合物11a和11d具有BGT1选择性，但抑制作用不强。
We previously designed and synthesized a series of cyclopropane-based conformationally restricted analogues of γ-aminobutyric acid (GABA). The study demonstrated that the critical conformation of the analogues that selectively active to betaine/GABA transporter 1 (BGT1) subtype is thetrans-syn-form, in which the amino and carboxyl groups are intrans-configuration and the cyclopropane ring and the carboxyl group are insyn-arrangement. In this study, we designed and synthesized cyclopropane-based GABA analogues, which were conformationally restricted in thetrans-syn-form by cyclopropylic strain based on the stereochemistry of the carbon adjacent to cyclopropane. Their conformation was confirmed as thesyn-form by calculations and NMR studies, and their pharmacological evaluation clarified that compounds11aand11dhad the BGT1 selectivity, although their inhibitory effects were insufficient.