دورية أكاديمية
Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1.
العنوان: | Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1. |
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المؤلفون: | Kickinger S; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Department of Pharmaceutical Science, University of Vienna, Vienna, Austria., Lie MEK; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Suemasa A; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Al-Khawaja A; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Fujiwara K; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Watanabe M; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Wilhelmsen KS; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Falk-Petersen CB; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Frølund B; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Shuto S; Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan., Ecker GF; Department of Pharmaceutical Science, University of Vienna, Vienna, Austria., Wellendorph P; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. |
المصدر: | Frontiers in chemistry [Front Chem] 2021 Sep 14; Vol. 9, pp. 736457. Date of Electronic Publication: 2021 Sep 14 (Print Publication: 2021). |
نوع المنشور: | Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 101627988 Publication Model: eCollection Cited Medium: Print ISSN: 2296-2646 (Print) Linking ISSN: 22962646 NLM ISO Abbreviation: Front Chem Subsets: PubMed not MEDLINE |
أسماء مطبوعة: | Original Publication: Lausanne : Frontiers Media S.A., [2013]- |
مستخلص: | The betaine/GABA transporter 1 (BGT1) is a member of the GABA transporter (GAT) family with still elusive function, largely due to a lack of potent and selective tool compounds. Based on modeling, we here present the design, synthesis and pharmacological evaluation of five novel conformationally restricted cyclic GABA analogs related to the previously reported highly potent and selective BGT1 inhibitor (1 S ,2 S ,5 R )-5-aminobicyclo[3.1.0]hexane-2-carboxylic acid (bicyclo-GABA). Using [ 3 H]GABA radioligand uptake assays at the four human GATs recombinantly expressed in mammalian cell lines, we identified bicyclo-GABA and its N -methylated analog ( 2 ) as the most potent and selective BGT1 inhibitors. Additional pharmacological characterization in a fluorescence-based membrane potential assay showed that bicyclo-GABA and 2 are competitive inhibitors, not substrates, at BGT1, which was validated by a Schild analysis for bicyclo-GABA (p K Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Kickinger, Lie, Suemasa, Al-Khawaja, Fujiwara, Watanabe, Wilhelmsen, Falk-Petersen, Frølund, Shuto, Ecker and Wellendorph.) |
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معلومات مُعتمدة: | W 1232 Austria FWF_ Austrian Science Fund FWF |
فهرسة مساهمة: | Keywords: BGT1; GABA transporter; SLC6 neurotransmitter transporters; bicyclo-GABA; binding mode analysis; competitive inhibition; computational chemistry; molecular docking, molecular dynamics |
تواريخ الأحداث: | Date Created: 20211001 Latest Revision: 20220727 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC8476755 |
DOI: | 10.3389/fchem.2021.736457 |
PMID: | 34595152 |
قاعدة البيانات: | MEDLINE |
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