Structure–Activity Relationships for Negative Allosteric mGluR5 Modulators

Authors

  • Dr. Birgitte H. Kaae,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    2. Radiometer Innovation, Radiometer Medical Aps, Åkandevej 21, 2700 Brønshøj (Denmark)
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  • Dr. Kasper Harpsøe,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Trine Kvist,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Dr. Jesper M. Mathiesen,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Christina Mølck,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Dr. David Gloriam,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Hermogenes N. Jimenez,

    1. ST-1 Glutamate Biology, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652-1431 (USA)
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  • Michelle A. Uberti,

    1. ST-1 Glutamate Biology, Lundbeck Research USA, 215 College Road, Paramus, NJ 07652-1431 (USA)
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  • Søren M. Nielsen,

    1. Molecular Pharmacology, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
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  • Birgitte Nielsen,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Prof. Hans Bräuner-Osborne,

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Per Sauerberg,

    1. Diabetes Protein & Peptide Chemistry, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv (Denmark)
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  • Dr. Rasmus P. Clausen,

    Corresponding author
    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
    • Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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  • Dr. Ulf Madsen

    1. Department of Molecular Drug Research, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark)
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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.

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