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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics / chemical synthesis
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Analgesics / chemistry
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Analgesics / pharmacology
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Animals
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Binding Sites
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Excitatory Postsynaptic Potentials
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Female
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HEK293 Cells
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Hippocampus / drug effects
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Hippocampus / physiology
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Humans
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In Vitro Techniques
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Male
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Models, Molecular
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Neuralgia / drug therapy
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Neuralgia / physiopathology
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Oocytes / drug effects
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Oocytes / physiology
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Patch-Clamp Techniques
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Peripheral Nerve Injuries / physiopathology
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Phenanthrenes / chemical synthesis*
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Phenanthrenes / chemistry
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Phenanthrenes / pharmacology
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Point Mutation
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Protein Subunits / antagonists & inhibitors
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Rats
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Rats, Wistar
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Receptors, Kainic Acid / antagonists & inhibitors*
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Receptors, Kainic Acid / genetics
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
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Receptors, N-Methyl-D-Aspartate / physiology
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Recombinant Proteins / antagonists & inhibitors
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Stereoisomerism
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Structure-Activity Relationship
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Xenopus
Substances
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1-(9-iodophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid
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Analgesics
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Gluk1 kainate receptor
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Phenanthrenes
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Piperazines
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Protein Subunits
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Receptors, Kainic Acid
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Receptors, N-Methyl-D-Aspartate
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Recombinant Proteins