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

MW Irvine, BM Costa, DP Dlaboga, GR Culley, RP Hulse, CL Scholefield, PT Atlason, G Fang, RJ Eaves, RM Morley, MB Mayo-Martin, M Amici, ZA Bortolotto, LF Donaldson, GL Collingridge, E Molnar, DT Monaghan, DE Jane

Research output: Contribution to journalArticle (Academic Journal)

13 Citations (Scopus)

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 contributionPiperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors
Original languageEnglish
Pages (from-to)327 - 341
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
Early online date24 Nov 2011
DOIs
Publication statusPublished - 2012

Bibliographical note

Publisher: ACS Publications

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