Selective mGAT2 (BGT-1) GABA Uptake Inhibitors: Design, Synthesis, and Pharmacological Characterization

Abstract

β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1-4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound 17b displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors.

Structure activity relationship of selective GABA uptake inhibitors

“…10 In general, the inhibitory activities of the compounds vary on all GABA transporter subtypes and the activity can be sensitive to stereochemistry and the nature of the side chain (Table 1 and 2). …”

“…10 In the current study, we extend the investigation of structure activity relationships for these compounds, by making the β-amino acid enantiomers separately, introducing variation in the lipophilic aromatic part and probing new amino acids.…”

“…10 The compounds were derived from the clinically approved and GAT-1 selective inhibitor Tiagabine (1), a lipophilic diaromatic derivative of the classical inhibitor (R)-nipecotic acid. A majority of the reported GABA transport inhibitors are lipophilic diaromatic derivatives of the GABA transporters substrates nipecotic acid and the areca nut alkaloid guvacine.…”

The Subcellular Localization of GABA Transporters and Its Implication for Seizure Management

“…This underlines the above mentioned theory that in order to achieve a synergistic anticonvulsant activity GATs localized synaptically and extrasynaptically need to be inhibited simultaneously [1]. A recent study by Vogensen et al [35] has investigated a new selective BGT1 inhibitor [4,4-Bis(3-methylthien-2-yl)but-3-enyl](2-carboxycyclohex-2-enyl)methylammonium Chloride, compound 17b). An isobologram study was undertaken to investigate whether tiagabine and compound 17b would interact synergistically as one would expect based on the hypothesis that if BGT1 is inhibited by compound 17b and GAT1 is inhibited by tiagabine then both the extrasynaptic and synaptic GABA levels, respectively would rise and a synergistic anticonvulsant effect would be observed.…”

Bicyclic β-amino acids

“…Derivatives of 31/32 with the norbornane ring system conserved also found their application in medicinal chemistry, e. g. in design of tromboxane A 2 receptor antagonist S-145 (90) (orally active as calcium salt), 39, 40, 72 nanomolar VLA-4 antagonist (91), 37 potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity (92), 73 and GABA uptake inhibitors. 74 It is interesting to note that θ torsion angle had dramatic influence on the biological activity of 92 and its analogues, being optimal for 92. Apart from the use in medicinal chemistry, amino acids 31 -34 found their application in other areas.…”