CGX-1007, a 17-amino
acid polypeptide isolated from the
venom of Conus geographus, is a novel
NMDA receptor antagonist that is selective for the NR2B subunit.
CI-1041 (
PD 196860; Co 200461) is a novel, orally available NR2B selective antagonist. Both compounds possess
anticonvulsant activity in a variety of well-established animal seizure models. The present study was designed to assess the effects of
CGX-1007 and
CI-1041 on the acquisition and expression of kindled
seizures. In the corneal kindled rat,
CGX-1007 [Epilepsia 36 (1998) 39] and
CI-1041, administered p.o., 2h prior to the kindling stimulation displayed time- and dose-dependent block of fully expressed corneal kindled
seizures (ED50 = 300 pmol and 2.5mg/kg for CGX-1007 and CI-1041, respectively). In amygdala kindled rats, acute treatment with
CGX-1007 blocked the secondarily generalized kindled seizure in a dose-dependent manner. Complete protection against the secondarily
generalized seizure was only observed at a dose that produced behavioral impairment (4 nmol). Acute treatment with
CI-1041 did not provide any notable protection against secondarily
generalized seizures. Neither compound provided protection against the focal kindled seizure. Chronic i.c.v. infusion of
CGX-1007 or chronic
oral administration of
CI-1041 did not delay the acquisition of amygdala kindling. The results from these studies suggest that
NMDA receptors containing the NR2B subunit may contribute to the expression of fully kindled secondarily
generalized seizures; however, they appear less important for the development of kindling. The differential results obtained with
CGX-1007 and
CI-1041 suggest that several classes of mechanistically distinct NR2B antagonists may exist and that
CGX-1007 may be less specific as a NR2B receptor antagonist than initially reported.