Functional characterization of Tet-AMPA [tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic acid] analogues at ionotropic glutamate receptors GluR1-GluR4. The molecular basis for the functional selectivity profile of 2-Bn-Tet-AMPA

Anders A. Jensen, Thomas Christesen, Ulrik Bølcho, Jeremy R Greenwood, Giovanna Postorino, Stine B Vogensen, Tommy N Johansen, Jan Egebjerg, Hans Bräuner-Osborne, Rasmus P Clausen

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    14 Citations (Scopus)

    Abstract

    Four 2-substituted Tet-AMPA [Tet = tetrazolyl, AMPA = 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] analogues were characterized functionally at the homomeric AMPA receptors GluR1i, GluR2Qi, GluR3i, and GluR4i in a Fluo-4/Ca2+ assay. Whereas 2-Et-Tet-AMPA, 2-Pr-Tet-AMPA, and 2-iPr-Tet-AMPA were nonselective GluR agonists, 2-Bn-Tet-AMPA exhibited a 40-fold higher potency at GluR4i than at GluR1i. Examination of homology models of the S1-S2 domains of GluR1 and GluR4 containing 2-Bn-Tet-AMPA suggested four nonconserved residues in a region adjacent to the orthosteric site as possible determinants of the GluR4i/GluR1i selectivity. In a mutagenesis study, doubly mutating M686V/I687A in GluR1i in combination with either D399S or E683A increased both the potency and the maximal response of 2-Bn-Tet-AMPA at this receptor to levels similar to those elicited by the agonist at GluR4i. The dependence of the novel selectivity profile of 2-Bn-Tet-AMPA upon residues located outside of the orthosteric site underlines the potential for developing GluR subtype selective ligands by designing compounds with substituents that protrude beyond the (S)-Glu binding pocket.
    Original languageEnglish
    JournalJournal of Medicinal Chemistry
    Volume50
    Issue number17
    Pages (from-to)4177-4185
    Number of pages9
    ISSN0022-2623
    DOIs
    Publication statusPublished - 2007

    Keywords

    • Aniline Compounds
    • Animals
    • Binding Sites
    • Cell Line
    • Female
    • Fluorescent Dyes
    • Humans
    • Isoxazoles
    • Models, Molecular
    • Mutation
    • Oocytes
    • Patch-Clamp Techniques
    • Propionic Acids
    • Rats
    • Receptors, AMPA
    • Sequence Homology, Amino Acid
    • Stereoisomerism
    • Structure-Activity Relationship
    • Tetrazoles
    • Thermodynamics
    • Xanthenes
    • Xenopus
    • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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