The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells.
The patch-clamp technique was used to measure currents passing through K+ channels in neuronal cell preparations. Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) activated a K+ conductance in slightly depolarized NG108-15 neuronal cells in a dose-dependent manner (0.1-10 microM). At the K+ reversal potential, no current could be elicited and in hyperpolarized cells the current was reversed. A similar current was elicited in primary cultures of mouse cortical neurones and in differentiated hNT cells, a cell line derived from human neuronal cells. At higher concentrations, retigabine also partially blocked voltage activated K+ currents. None of the tested anticonvulsants, phenytoin, carbamazepine and valproate and none of the K+ channel openers cromakalim, diazoxide and pinacidil exerted a similar effect. The current was not affected by the K+ channel blocker glibenclamide (10 microM) but was fully blocked by application of Ba2+ (10.8 mM). Exchange of K+ with cesium in the intracellular space also fully abolished the current. It can be expected that the K+ channel opening effect contributes to the anticonvulsant activity of retigabine.
Rundfeldt
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Department of Pharmacology, Arzneimittelwerk Dresden GmbH, Corporate R & D, Radebeul, Germany.
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists*; D051381:Rats; D014407:Tumor Cells, Cultured
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; D015221:Potassium Channels; C101866:ezogabine