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

ACS Chem Neurosci. 2016 May 18;7(5):534-9. doi: 10.1021/acschemneuro.5b00311. Epub 2016 Mar 3.

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; aspartate derivatives; asymmetric synthesis; inhibitors; isoform selectivity; photoaffinity probes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid / analogs & derivatives*
  • Aspartic Acid / chemical synthesis
  • Aspartic Acid / pharmacology
  • Chemistry, Pharmaceutical
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Transporter 1 / antagonists & inhibitors*
  • Excitatory Amino Acid Transporter 1 / metabolism
  • Excitatory Amino Acid Transporter 3 / antagonists & inhibitors*
  • Excitatory Amino Acid Transporter 3 / metabolism
  • Glutamate Plasma Membrane Transport Proteins / antagonists & inhibitors*
  • Glutamate Plasma Membrane Transport Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Photoaffinity Labels / chemical synthesis*
  • Photoaffinity Labels / pharmacology
  • Stereoisomerism

Substances

  • (2S,3S)-3-(3-(4-(trifluoromethyl)benzoylamino)benzyloxy)aspartate
  • Excitatory Amino Acid Transporter 1
  • Excitatory Amino Acid Transporter 3
  • Glutamate Plasma Membrane Transport Proteins
  • Photoaffinity Labels
  • SLC1A1 protein, human
  • SLC1A2 protein, human
  • SLC1A3 protein, human
  • Aspartic Acid