Cyclopropane-based conformational restriction of GABA by a stereochemical diversity-oriented strategy: Identification of an efficient lead for potent inhibitors of GABA transports |
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| Authors: | Kazuaki Nakada Mamie Yoshikawa Soichiro Ide Akihiro Suemasa Shuhei Kawamura Takaaki Kobayashi Eiji Masuda Yoshihiko Ito Wataru Hayakawa Takahiro Katayama Shizuo Yamada Mitsuhiro Arisawa Masabumi Minami Satoshi Shuto |
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| Institution: | 1. Laboratory of Organic Chemistry for Drug Development, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;2. Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;3. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Sapporo 060-0812, Japan;4. Graduate School of Pharmaceutical Sciences, University of Shizuoka, Yada, Shizuoka 422-8526, Japan |
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| Abstract: | A series of cyclopropane-based conformationally restricted γ-aminobutyric acid (GABA) analogs with stereochemical diversity, that is, the trans- and cis-2,3-methano analogs Ia and Ib and their enantiomers ent-Ia and ent-Ib, and also the trans- and cis-3,4-methano analogs IIa and IIb and their enantiomers ent-IIa and ent-Iib, were synthesized from the chiral cyclopropane units Type-a and Type-b that we developed. These analogs were systematically evaluated with four GABA transporter (GAT) subtypes. The trans-3,4-methano analog IIa had inhibitory effects on GAT3 (IC50 = 23.9 μM) and betaine-GABA transporter1 (5.48 μM), indicating its potential as an effective lead compound for the development of potent GAT inhibitors due to its hydrophilic and low molecular weight properties and excellent ligand efficiency. |
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| Keywords: | GABA transporter GAT3 BGT1 Cyclopropane Conformational restriction |
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