Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects
| العنوان: | Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects |
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| المؤلفون: | Arne Schousboe, Rasmus P. Clausen, Stefanie Kickinger, Jonas Skovgaard-Petersen, Maria E. K. Lie, Gerhard F. Ecker, Petrine Wellendorph, H. Steve White |
| المصدر: | Lie, M E K, Kickinger, S, Skovgaard-Petersen, J, Ecker, G F, Clausen, R P, Schousboe, A, White, H S & Wellendorph, P 2020, ' Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects ', Neurochemical Research, vol. 45, pp. 1551–1565 . https://doi.org/10.1007/s11064-020-03017-y Neurochemical Research |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, GABA Plasma Membrane Transport Proteins, Tiagabine, Mice, Transgenic, GABA uptake, CHO Cells, Pharmacology, Biochemistry, Epilepsy, Reflex, Protein Structure, Secondary, GABA transporter 1, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, 0302 clinical medicine, Betaine, Cricetulus, Seizures, medicine, GABA transporter, Animals, Humans, Q299L, Binding site, Original Paper, Epilepsy, biology, General Medicine, Cyclohexanecarboxylic acid, 030104 developmental biology, HEK293 Cells, Treatment Outcome, chemistry, Acoustic Stimulation, GAT1, Docking (molecular), Cell culture, biology.protein, Anticonvulsants, Homology modelling, 030217 neurology & neurosurgery, medicine.drug, Protein Binding |
| الوصف: | Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine (Gabitril®). Synergistic anti-seizure effects achieved by inhibition of both GAT1 and the betaine/GABA transporter (BGT1) by tiagabine and EF1502, compared to tiagabine alone, suggest BGT1 as a target in epilepsy. Yet, selective BGT1 inhibitors are needed for validation of this hypothesis. In that search, a series of BGT1 inhibitors typified by (1R,2S)-2-((4,4-bis(3-methylthiophen-2-yl)but-3-en-yl)(methyl)amino)cyclohexanecarboxylic acid (SBV2-114) was developed. A thorough pharmacological characterization of SBV2-114 using a cell-based [3H]GABA uptake assay at heterologously expressed BGT1, revealed an elusive biphasic inhibition profile with two IC50 values (4.7 and 556 μM). The biphasic profile was common for this structural class of compounds, including EF1502, and was confirmed in the MDCK II cell line endogenously expressing BGT1. The possibility of two binding sites for SBV2-114 at BGT1 was assessed by computational docking studies and examined by mutational studies. These investigations confirmed that the conserved residue Q299 in BGT1 is involved in, but not solely responsible for the biphasic inhibition profile of SBV2-114. Animal studies revealed anti-seizure effects of SBV2-114 in two mouse models, supporting a function of BGT1 in epilepsy. However, as SBV2-114 is apparent to be rather non-selective for BGT1, the translational relevance of this observation is unknown. Nevertheless, SBV2-114 constitutes a valuable tool compound to study the molecular mechanism of an emerging biphasic profile of BGT1-mediated GABA transport and the putative involvement of two binding sites for this class of compounds. Electronic supplementary material The online version of this article (10.1007/s11064-020-03017-y) contains supplementary material, which is available to authorized users. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3be1e5b0f009359dee573c6df3162134 https://curis.ku.dk/portal/da/publications/pharmacological-characterization-of-a-betainegaba-transporter-1-bgt1-inhibitor-displaying-an-unusual-biphasic-inhibition-profile-and-antiseizure-effects(f58627b3-6c59-4d36-ad00-48d86bf6a034).html |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....3be1e5b0f009359dee573c6df3162134 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |