Suemasa Akihiro, Watanabe Mizuki, Kobayashi Takaaki, Suzuki Hiroe, Fukuda Hayato, Minami Masabumi, Shuto Satoshi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Bioorg Med Chem Lett. 2018 Nov 1;28(20):3395-3399. doi: 10.1016/j.bmcl.2018.08.031. Epub 2018 Aug 27.
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 the trans-syn-form, in which the amino and carboxyl groups are in trans-configuration and the cyclopropane ring and the carboxyl group are in syn-arrangement. In this study, we designed and synthesized cyclopropane-based GABA analogues, which were conformationally restricted in the trans-syn-form by cyclopropylic strain based on the stereochemistry of the carbon adjacent to cyclopropane. Their conformation was confirmed as the syn-form by calculations and NMR studies, and their pharmacological evaluation clarified that compounds 11a and 11d had the BGT1 selectivity, although their inhibitory effects were insufficient.
我们之前设计并合成了一系列基于环丙烷的γ-氨基丁酸（GABA）构象受限类似物。研究表明，对甜菜碱/GABA转运体1（BGT1）亚型具有选择性活性的类似物的关键构象是反式-顺式形式，其中氨基和羧基处于反式构型，环丙烷环和羧基处于顺式排列。在本研究中，我们设计并合成了基于环丙烷的GABA类似物，基于与环丙烷相邻碳的立体化学，通过环丙基应变将其构象限制在反式-顺式形式。通过计算和核磁共振研究证实它们的构象为顺式形式，并且它们的药理学评价表明化合物11a和11d具有BGT1选择性，尽管它们的抑制作用不足。
