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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 N1-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.
Translated title of the contribution | Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors |
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Original language | English |
Pages (from-to) | 327 - 341 |
Number of pages | 15 |
Journal | Journal of Medicinal Chemistry |
Volume | 55 |
Issue number | 1 |
Early online date | 24 Nov 2011 |
DOIs | |
Publication status | Published - 2012 |
Bibliographical note
Publisher: ACS PublicationsFingerprint
Dive into the research topics of 'Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors'. Together they form a unique fingerprint.Projects
- 4 Finished
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ELUCIDATION OF THE ROLE OF KAINATE RECEPTOR SUBTYPES IN HIPPOCAMPAL SYNAPTIC FUNCTION USING NOVEL PHARMACOLOGICAL TOOLS
Jane, D. E. (Principal Investigator)
1/03/08 → 1/03/11
Project: Research
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DISCOVERING NOVEL SUBTYPE-SELECTIVE GLUTAMATE RECEPTOR ANTAGONISTS FOR THE STUDY OF HIPPOCAMPUL SYNAPTIC PLASTICITY
Jane, D. E. (Principal Investigator)
1/01/08 → 1/01/13
Project: Research
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MECHANISMS OF NMDA RECEPTOR DEPENDANT LTP AND LTD IN THE HIPPOCAMPUS
Collingridge, G. L. (Principal Investigator)
1/01/08 → 1/04/13
Project: Research