Investigations into the mechanism of action of the new anticonvulsant retigabine. Interaction with GABAergic and glutamatergic neurotransmission and with voltage gated ion channels

Abstract

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)phenyl) carbamic acid ethyl ester, CAS 150812-12-7, D-23129) is a novel anticonvulsant currently undergoing phase II clinical trials. The compound was shown to possess broad spectrum and potent anticonvulsant properties both in vitro and in vivo. The mechanism of action of this drug is currently not fully understood. In previous studies a potent opening effect on K+ channels and an increased release of newly synthesized gamma-aminobutyric acid (GABA) were reported. The aim of this study was to investigate the interaction of retigabine with GABA, kainate and N-methyl-D-aspartate (NMDA) induced currents as well as with voltage gated Na+ and Ca++ channels. Retigabine concentration dependently potentiated GABA induced currents in rat cortical neurones. Significant effects were only seen with concentrations of 10 mumol/l and above. The action of retigabine was not antagonised by flumazenil indicating interaction with other than benzodiazepine binding sites. In comparison with the K+ channel opening effect which can be seen at concentrations as low as 0.1 mumol/l the contribution of this mechanism to the anticonvulsant activity of retigabine may be minor. Inhibitory effects observed on voltage activated Na+ and Ca++ channels as well as on kainate induced currents were only observed at the highest concentration tested (100 mumol/l) and can be considered non specific. No significant interaction with NMDA induced currents was observed.