The effect of CGX-1007 and CI-1041, novel NMDA receptor antagonists, on kindling acquisition and expression.
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.
Barton
Matthew E
ME
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, University of Utah, 20 S 2030 E, RM 408, Salt Lake City, UT 84112, USA.
White
H Steve
HS
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D020916:Conotoxins / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology
D001583:Benzoxazoles; D020916:Conotoxins; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C481484:besonprodil; C055407:conotoxin GV