Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects

• DOI: 10.1007/s11064-020-03017-y
• Publication Date: 2020-04-04T17:04:18Z
• Authors: Maria E. K. Lie; Stefanie Kickinger; Jonas Skovgaard-P...; Gerhard F. Ecker; Rasmus P. Clausen; Arne Schousboe; H. Steve White; Petrine Wellendorph
• Keywords: Tiagabine; GABA transporter; Betaine; Docking (animal)

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 inhibition of both GAT1 and betaine/GABA (BGT1) EF1502, compared to alone, suggest BGT1 as a target epilepsy. Yet, selective inhibitors are needed for validation this hypothesis. In that search, series typified (1R,2S)-2-((4,4-bis(3-methylthiophen-2-yl)but-3-en-yl)(methyl)amino)cyclohexanecarboxylic (SBV2-114) was developed. A thorough pharmacological characterization SBV2-114 cell-based [3H]GABA assay at heterologously expressed BGT1, revealed an elusive biphasic profile with two IC50 values (4.7 556 μM). The common structural class compounds, including confirmed MDCK II cell line endogenously expressing BGT1. possibility binding sites assessed computational docking studies examined mutational studies. These investigations conserved residue Q299 is involved in, but not solely responsible SBV2-114. Animal mouse models, supporting function However, apparent rather non-selective translational relevance observation unknown. Nevertheless, constitutes valuable tool compound study molecular mechanism emerging BGT1-mediated transport putative involvement compounds.