Design and synthesis of cyclopropane-based conformationally restricted GABA analogues as selective inhibitors for betaine/GABA transporter 1. Issue 20 (1st November 2018)

• Record Type: Journal Article
• Authors: Suemasa, Akihiro; Watanabe, Mizuki; Kobayashi, Takaaki; Suzuki, Hiroe; Fukuda, Hayato; Minami, Masabumi; Shuto, Satoshi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 20(2018)
• Page Start: 3395
• Page End: 3399
• Publication Date: 2018-11-01
• Subjects: GABA -- BGT1 -- Cyclopropane -- Conformational restriction -- Selective inhibitor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.08.031
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: α-Substituted-β, γ-methano-GABA analogues were designed and synthesized. The conformation of these analogues was regulated to the trans-syn -form. The trans-syn -form of GABA analogues were critical for the BGT1 selectivity. Abstract: 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 compounds11a and11d had the BGT1 selectivity, although their inhibitory effects were insufficient.