Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3

Sebastien Alaux, Mie Kusk, Emanuelle Sagot, Jean Bolte, Anders A. Jensen, Hans Bräuner-Osborne, Thierry Gefflaut, Lennart Bunch

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    Abstract

    A series of nine L-2,4-syn-4-alkylglutamic acid analogues (1a-i) were synthesized in high yield and high enantiomeric excess (>99% ee) from their corresponding 4-substituted ketoglutaric acids (2a-i), using the enzyme aspartate aminotransferase (AAT) from pig heart or E. coli. The synthesized compounds were evaluated as potential ligands for the glutamate transporters EAAT1, EAAT2, and EAAT3 (excitatory amino acid transporter, subtypes 1-3) in the FLIPR membrane potential (FMP) assay. We found a distinct change in the pharmacological profile when the 4-methyl group (compound 1a, an EAAT1 substrate and EAAT2,3 inhibitor) was extended to a 4-ethyl group, compound 1b, as this analogue is an inhibitor at all three subtypes, EAAT1-3. Furthermore, we conclude that both large and bulky hydrophobic substituents in the 4-position of L-2,4-syn Glu are allowed by all three glutamate transporter subtypes EAAT1-3 while maintaining inhibitory activity.
    Original languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume48
    Issue number25
    Pages (from-to)7980-92
    Number of pages13
    ISSN0022-2623
    DOIs
    Publication statusPublished - 2005

    Keywords

    • Animals
    • Aspartate Aminotransferases
    • Cell Line
    • Excitatory Amino Acid Transporter 2
    • Excitatory Amino Acid Transporter 3
    • Glutamates
    • Humans
    • Ketoglutaric Acids
    • Membrane Potentials
    • Models, Molecular
    • Myocardium
    • Stereoisomerism
    • Structure-Activity Relationship
    • Swine

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