Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7.

Emanuelle Sagot, Darryl S Pickering, Xiaosui Pu, Michelle Umberti, Tine B Stensbøl, Birgitte Nielsen, Marion Chapelet, Jean Bolte, Thierry Gefflaut, Lennart Bunch

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    Abstract

    ( S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the central nervous system (CNS) activating the plethora of ionotropic Glu receptors (iGluRs) and metabotropic Glu receptors (mGluRs). In this paper, we present a chemo-enzymatic strategy for the enantioselective synthesis of five new Glu analogues 2a- f ( 2d is exempt) holding a functionalized substituent in the 4-position. Nine Glu analogues 2a- j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), kainic acid (KA), and N-methyl- d-aspartic acid (NMDA) receptors in rat synaptosomes as well as in binding assays at cloned rat iGluR5-7 subtypes. A detailed in silico study address as to why 2h is a high-affinity ligand at iGluR5-7 ( K i = 3.81, 123, 57.3 nM, respectively), while 2e is only a high affinity ligand at iGluR5 ( K i = 42.8 nM). Furthermore, a small series of commercially available iGluR ligands are characterized in iGluR5-7 binding.
    Original languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume51
    Issue number14
    Pages (from-to)4093-103
    ISSN0022-2623
    DOIs
    Publication statusPublished - 2008

    Bibliographical note

    Keywords: Amination; Animals; Glutamic Acid; Magnetic Resonance Spectroscopy; Mass Spectrometry; Rats; Receptors, Glutamate; Spectrophotometry, Infrared; Structure-Activity Relationship; Synaptosomes

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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