title: The relationship between sodium channel inhibition and anticonvulsant activity in a model of generalised seizure in the rat.
abstract: The development of novel anticonvulsant drugs with improved efficacy for the treatment of epilepsy is hindered by a lack of information regarding the quantitative relationship between target mechanism and in vivo efficacy. In the present study we have examined the correlation between the potency of structurally diverse compounds at voltage-gated sodium channels in vitro and their efficacy in a rodent model of acute generalised seizures induced by electroshock. We observed a significant correlation between the estimated affinity (Ki) of the compounds for the inactivated state of human recombinant Na(V)1.2 channels and the unbound brain concentration required for anticonvulsant efficacy. Furthermore, the data suggest that an unbound concentration equivalent to less than 50% of the Ki is sufficient for anticonvulsant effect. We noted that increasing sodium channel blocking potency was associated with increasing brain tissue binding and lipophilicity. These data suggest that there is a balance between sodium channel blocking potency in vitro and good pharmacokinetic characteristics necessary for anticonvulsant efficacy in vivo. Finally, we examined the sodium channel blocking potency of sodium valproate in relation to its anticonvulsant efficacy in vivo. We found that a higher unbound concentration of the drug in the brain was required for anticonvulsant efficacy than would be expected given its sodium channel blocking potency.
authors.affiliation: epartment of Molecular and Cellular Biology, Neuroscience Centre of Excellence for Drug Discovery, Medicines Research Centre, GlaxoSmithKline S.p.A., Via Fleming 4, Verona 37135, Italy. charles.h.large@gsk.com
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.forename: Adam
authors.initials: A
authors.lastname: Lucas
authors.forename: Corrado
authors.initials: C
authors.lastname: Carignani
authors.forename: Andrea
authors.initials: A
authors.lastname: Bradford
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Garbati
authors.forename: Ilaria
authors.initials: I
authors.lastname: Sartori
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Austin
authors.forename: Alberto
authors.initials: A
authors.lastname: Ruffo
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read