The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits.

Department of Pharmacology, Arzneimittelwerk Dresden GmbH, Corporate R&D, ASTA Medica Group, Meibetaner Strasse 35, D-01445, Radebeul, Germany. dr_chris.rundfeldt@astamedica.de

Retigabine (D-23129) is a novel antiepileptic compound with broad spectrum and potent anticonvulsant properties, both in vitro and in vivo. The compound was shown to activate a K(+) current in neuronal cells. The pharmacology of the induced current displays concordance with the published pharmacology of the M-channel, which recently was correlated to the KCNQ2/3 K(+) channel heteromultimere. We examined the effect of retigabine on KCNQ2/3 expressed in Chinese hamster ovary cells. The compound concentration-dependently activated a K(+) current in transfected cells clamped at -50 mV. The activation was induced by a shift of the opening threshold to more negative potentials. The effect was not mediated by an interaction with the cAMP modulatory site and could be partially blocked by the M-channel antagonist linopirdine. The data display that retigabine is the first described M-channel agonist and support the hypothesis that M-channel agonism is a new mode of action for anticonvulsant drugs. Since the function of this channel is reduced in a hereditary epilepsy syndrome, retigabine may be the first anticonvulsant to directly target the deficit observed in a channelopathy.

PMID: 10713399 [PubMed - indexed for MEDLINE]