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The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on NMDA receptor-mediated EPSCs.

Abstract
The N-methyl-D-aspartate (NMDA) receptor-gated ion channel is comprised of at least one NR1 subunit and any of four NR2 subunits (NR2A-D). The NR2 subunit confers different pharmacological and kinetic properties to the receptor. CGX-1007 (Conantokin G), a 17-amino acid polypeptide isolated from the venom of Conus geographus, is a novel NMDA receptor antagonist that is thought to be selective for the NR2B subunit. CGX-1007 has been reported to have highly potent, broad-spectrum anticonvulsant activity in animal seizure models. CI-1041 is an investigational compound, which also possesses anticonvulsant activity and has been shown to be highly selective for NR2B containing NMDA receptors. Although both CI-1041 and CGX-1007 are reportedly NR2B specific antagonists, they differ in their ability to block amygdala-kindled seizures, suggesting that the mechanism of action of these compounds differs. The present study was designed to test the hypothesis that CI-1041 and CGX-1007 would differentially modulate the function of NMDA receptors at excitatory synapses. Using the whole cell patch clamp technique, CGX-1007 and CI-1041 were found to block CA1 pyramidal cell, NMDA receptor-mediated excitatory postsynaptic currents (N-EPSCs) in a concentration-dependent manner in hippocampal slices from P4-P6 animals. In contrast, only CGX-1007 decreased NMDA receptor-mediated EPSC peak amplitude in slices from adult animals. The CGX-1007 block of peak amplitude was accompanied by a similar concentration-dependent decrease in decay kinetics of NMDA receptor-mediated EPSCs. These results suggest that while CI-1041 may be selective for NMDA receptors containing the NR2B subunit, CGX-1007 appears to be less selective than previously reported.
AuthorsMatthew E Barton, H Steve White, Karen S Wilcox
JournalEpilepsy research (Epilepsy Res) Vol. 59 Issue 1 Pg. 13-24 (Mar 2004) ISSN: 0920-1211 [Print] Netherlands
PMID15135163 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Benzoxazoles
  • Conotoxins
  • Excitatory Amino Acid Antagonists
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • besonprodil
  • conotoxin GV
Topics
  • Animals
  • Benzoxazoles (pharmacology)
  • Conotoxins (pharmacology)
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists (pharmacology)
  • Excitatory Postsynaptic Potentials (drug effects, physiology)
  • Hippocampus (drug effects, physiology)
  • In Vitro Techniques
  • Male
  • Piperidines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors, physiology)

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