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Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization

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Abstract

A series of analogues of the glutamate receptor ligands (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and AMOA were synthesized in which the 3-hydroxyisoxazole moiety was exchanged for a 3-hydroxypyrazole moiety. This exchange enables further substitution at the additional nitrogen atom in the heterocyclic core. Several of the analogues have activity at AMPA receptors equipotent to the antagonist ATPO, demonstrating that additional substitution can be accommodated in the antagonist binding site. Modelling studies offer an explanation for the pharmacological pattern observed for the compounds and suggest that this scaffold may be developed further to obtain subtype selective antagonists.

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Acknowledgments

The Lundbeck Foundation, the Hørslev Foundation and the University of Copenhagen Programme of Excellence GluTarget are gratefully acknowledged for financial support. The technical assistance of Flemming Hansen, Department of Chemistry, University of Copenhagen, with collecting X-ray data is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, Copenhagen, DK-2100, Denmark

    Lars Jørgensen, Birgitte Nielsen, Darryl S. Pickering, Anders S. Kristensen, Karla Frydenvang, Ulf Madsen & Rasmus P. Clausen

Authors
  1. Lars Jørgensen
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  2. Birgitte Nielsen
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  3. Darryl S. Pickering
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  4. Anders S. Kristensen
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  5. Karla Frydenvang
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  6. Ulf Madsen
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  7. Rasmus P. Clausen
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Corresponding authors

Correspondence to Ulf Madsen or Rasmus P. Clausen.

Additional information

Special Issue: In honor of Krogsgaard-Larsen.

Ulf Madsen and Rasmus P. Clausen have contributed equally to this work.

Electronic supplementary material

Supporting information is available containing experimental details for the synthesis and characterization of compounds 17, 18, 19a, 19b, 20, 21, 22a, 22b, 23–28, 29a, 29b, 30a, 30b, 31a, 31b, 34–36, and for the X-ray crystallographic data collection and structure solution.

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Jørgensen, L., Nielsen, B., Pickering, D.S. et al. Analogues of 3-Hydroxyisoxazole-Containing Glutamate Receptor Ligands Based on the 3-Hydroxypyrazole-Moiety: Design, Synthesis and Pharmacological Characterization. Neurochem Res 39, 1895–1905 (2014). https://doi.org/10.1007/s11064-014-1332-0

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  • DOI: https://doi.org/10.1007/s11064-014-1332-0

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