title: Piperazine-2,3-dicarboxylic acid derivatives as dual antagonists of NMDA and GluK1-containing kainate receptors.
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.
authors: MRC Centre for Synaptic Plasticity, University of Bristol, Medical Sciences Building, University Walk, Bristol, BS8 1TD, U.K.
authors: Mark W
authors: MW
authors: Irvine
authors: Blaise M
authors: BM
authors: Costa
authors: Daniel
authors: D
authors: Dlaboga
authors: Georgia R
authors: GR
authors: Culley
authors: Richard
authors: R
authors: Hulse
authors: Caroline L
authors: CL
authors: Scholefield
authors: Palmi
authors: P
authors: Atlason
authors: Guangyu
authors: G
authors: Fang
authors: Richard
authors: R
authors: Eaves
authors: Richard
authors: R
authors: Morley
authors: Maria B
authors: MB
authors: Mayo-Martin
authors: Mascia
authors: M
authors: Amici
authors: Zuner A
authors: ZA
authors: Bortolotto
authors: Lucy
authors: L
authors: Donaldson
authors: Graham L
authors: GL
authors: Collingridge
authors: Elek
authors: E
authors: Molnár
authors: Daniel T
authors: DT
authors: Monaghan
authors: David E
authors: DE
authors: Jane
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D059348:Peripheral Nerve Injuries / Q000503:physiopathology; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017354:Point Mutation; D021122:Protein Subunits / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
chemical_list: D000700:Analgesics; D010616:Phenanthrenes; D010879:Piperazines; D021122:Protein Subunits; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C570913:1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid