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.