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Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1.

التفاصيل البيبلوغرافية
العنوان: Molecular Determinants and Pharmacological Analysis for a Class of Competitive Non-transported Bicyclic Inhibitors of the Betaine/GABA Transporter BGT1.
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 B value of 6.4). To further elaborate on the selectivity profile both compounds were tested at recombinant α 1 β 2 γ 2 GABA A receptors. Whereas bicyclo-GABA showed low micromolar agonistic activity, the N -methylated 2 was completely devoid of activity at GABA A receptors. To further reveal the binding mode of bicyclo-GABA and 2 binding hypotheses of the compounds were obtained from in silico -guided mutagenesis studies followed by pharmacological evaluation at selected BGT1 mutants. This identified the non-conserved BGT1 residues Q299 and E52 as the molecular determinants driving BGT1 activity and selectivity. The binding mode of bicyclo-GABA was further validated by the introduction of activity into the corresponding GAT3 mutant L314Q (38 times potency increase cf. wildtype). Altogether, our data reveal the molecular determinants for the activity of bicyclic GABA analogs, that despite their small size act as competitive inhibitors of BGT1. These compounds may serve as valuable tools to selectively and potently target BGT1 in order to decipher its elusive pharmacological role in the brain and periphery such as the liver and kidneys.
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
الوصف
تدمد:2296-2646
DOI:10.3389/fchem.2021.736457