Structure-activity relationships for negative allosteric mGluR5 modulators

Birgitte H Kaae, Kasper Harpsøe, Trine Kvist, Jesper M Mathiesen, Christina Mølck, David E Gloriam, Hermogenes N Jimenez, Michelle A Uberti, Søren M Nielsen, Birgitte Nielsen, Hans Bräuner-Osborne, Per Sauerberg, Rasmus Prætorius Clausen, Ulf Madsen

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    15 Citations (Scopus)

    Abstract

    A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.
    Original languageEnglish
    JournalChemMedChem
    Volume7
    Issue number3
    Pages (from-to)440-451
    ISSN1860-7179
    DOIs
    Publication statusPublished - 2012

    Bibliographical note

    Keywords: allosteric modulators; cross-coupling; mGluR5; molecular modeling; structure–activity relationships

    Keywords

    • Former Faculty of Pharmaceutical Sciences

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