title: Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons.
abstract: Carisbamate (RWJ-333369; (S)-2-O-carbamoyl-1-o-chlorophenyl-ethanol) is a novel investigational antiepileptic drug that exhibits a broad-spectrum of activity in a number of animal models of seizure and drug refractory epilepsy. In an effort to understand the molecular mechanism by which carisbamate produces its antiepileptic actions, we studied its effects on the function of voltage-gated, rat brain sodium and potassium channels and on the repetitive firing of action potentials in cultured rat hippocampal neurons. In whole-cell patch clamp recording, carisbamate resulted in a concentration-, voltage- and use-dependent inhibition of rat Nav1.2, with an IC(50) value of 68 microM at -67 mV. In rat hippocampal neurons, carisbamate similarly blocked voltage-gated sodium channels, with an IC(50) value of 89 microM at -67 mV, and inhibited repetitive firing of action potentials in a concentration-dependent manner (by 46% at 30 microM and 87% at 100 microM, respectively). Carisbamate had no effect on the steady-state membrane potential or voltage-gated potassium channels (K(v)) in these neurons. These inhibitory effects of carisbamate occurred at therapeutically relevant concentrations in vivo, raising the possibility that block of voltage-gated sodium channels by carisbamate contributes to its antiepileptic activity.
authors.affiliation: Analgesics Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, PA 19477-0776, USA. yliu10@its.jnj.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: George J
authors.initials: GJ
authors.lastname: Yohrling
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Tasha L
authors.initials: TL
authors.lastname: Hutchinson
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Brenneman
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
authors.forename: Boyu
authors.initials: B
authors.lastname: Zhao
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000494:pharmacology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; C518914:S-2-O-carbamoyl-1-o-chlorophenyl-ethanol; D026941:Sodium Channel Blockers; D010672:Phenytoin