Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors

Mark W. Irvine, Blaise M. Costa, Daniel Dlaboga, Georgia R. Culley, Richard Hulse, Caroline L. Scholefield, Palmi Atlason, Guangyu Fang, Richard Eaves, Richard Morley, Maria B. Mayo-Martin, Mascia Amici, Zuner A. Bortolotto, Lucy Donaldson, Graham L. Collingridge, Elek Molnár, Daniel T. Monaghan, David E. Jane

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Competitive N-methyl-d-aspartate receptor (NMDAR) antagonists bind to the GluN2 subunit, of which there are four types (GluN2A-D). We report that some N 1-substituted derivatives of cis-piperazine-2,3-dicarboxylic acid display improved relative affinity for GluN2C and GluN2D versus GluN2A and GluN2B. These derivatives also display subtype selectivity among the more distantly related kainate receptor family. Compounds 18i and (-)-4 were the most potent kainate receptor antagonists, and 18i was selective for GluK1 versus GluK2, GluK3 and AMPA receptors. Modeling studies revealed structural features required for activity at GluK1 subunits and suggested that S674 was vital for antagonist activity. Consistent with this hypothesis, replacing the equivalent residue in GluK3 (alanine) with a serine imparts 18i antagonist activity. Antagonists with dual GluN2D and GluK1 antagonist activity may have beneficial effects in various neurological disorders. Consistent with this idea, antagonist 18i (30 mg/kg ip) showed antinociceptive effects in an animal model of mild nerve injury.

Original languageEnglish (US)
Pages (from-to)327-341
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
DOIs
StatePublished - Jan 12 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Irvine, M. W., Costa, B. M., Dlaboga, D., Culley, G. R., Hulse, R., Scholefield, C. L., Atlason, P., Fang, G., Eaves, R., Morley, R., Mayo-Martin, M. B., Amici, M., Bortolotto, Z. A., Donaldson, L., Collingridge, G. L., Molnár, E., Monaghan, D. T., & Jane, D. E. (2012). Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors. Journal of Medicinal Chemistry, 55(1), 327-341. https://doi.org/10.1021/jm201230z