Ralitoline (CI-946) and CI-953 block sustained repetitive sodium action potentials in cultured mouse spinal cord neurons and displace batrachotoxinin A 20-alpha-benzoate binding in vitro.
Ralitoline and CI-953 are anticonvulsant compounds active in both maximal electroshock and kindling models of seizures with rodents. CI-953 (IC50 = 5 microM) and ralitoline (IC50 = 2 microM) both blocked sustained repetitive firing of sodium action potentials with effects on firing activity triggered by spontaneous excitatory postsynaptic potentials at higher concentrations. No effects on iontophoretic GABA and glutamate responses were noted. Both compounds inhibited the binding of tritiated batrachotoxinin A 20-alpha-benzoate ([3H]BTX-b) to rat brain synaptosomes with apparent Kd values of 29 microM (CI-953) and 25 microM (ralitoline). Our results suggest that effects on voltage-dependent sodium channels may underlie the anticonvulsant action of these compounds.
Rock
D M
DM
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner Lambert Company, Ann Arbor, MI 48105.
McLean
M J
MJ
Macdonald
R L
RL
Catterall
W A
WA
Taylor
C P
CP
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology*; D001496:Batrachotoxins / Q000378:metabolism*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology; D004827:Epilepsy / Q000188:drug therapy; D007700:Kinetics; D051379:Mice; D009474:Neurons / Q000187:drug effects; D010671:Phenylurea Compounds / Q000097:blood / Q000494:pharmacology*; D010672:Phenytoin / Q000494:pharmacology; D011869:Radioligand Assay; D015222:Sodium Channels / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology; D013574:Synaptosomes / Q000378:metabolism; D013844:Thiazoles / Q000097:blood / Q000494:pharmacology*
D000927:Anticonvulsants; D001496:Batrachotoxins; D010671:Phenylurea Compounds; D015222:Sodium Channels; D013844:Thiazoles; C070428:CI 953; D002220:Carbamazepine; D010672:Phenytoin; C031775:batrachotoxinin A 20-alpha-benzoate; C054894:Ralitoline