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Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Publication date 2016
Author Leuenberger Michele, Ritler Andreas, Simonin Alexandre, Hediger Matthias A., Lochner Martin,
Project Synthetic Neurochemistry - Introduction of Biophysical Tools into Ion Channels Using Chemical Approaches
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Original article (peer-reviewed)

Journal ACS Chemical Neuroscience
Volume (Issue) 7
Page(s) 534 - 539
Title of proceedings ACS Chemical Neuroscience
DOI 10.1021/acschemneuro.5b00311

Abstract

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-Benzylated L-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)-benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1−3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy. KEYWORDS: Glutamate transporters, asymmetric synthesis, inhibitors, aspartate derivatives, isoform selectivity, photoaffinity probes
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