Investigations into the mechanism of action of the new anticonvulsant retigabine

Retigabine (N-(2-amino-4-(4-fluorobenzylamino)phenyl carbamic acid ethyl es ter, CAS 150812-12-7, D-23129) is a novel anticonvulsant currently undergoi ng phase II clinical trials. The compound was shown to possess broad spectr um and potent anticonvulsant properties both in vitro and in vivo. The mech anism 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 o f this study was to investigate the interaction of retigabine with GABA, ka inate and N-methyl-D-aspartate (NMDA) induced currents as well as with volt age gated Na+ and Ca++ channels. Retigabine concentration dependently potentiated GABA induced currents in r at cortical neurones. Significant effects were only seen with concentration s of 10 mol/l and above. The action of retigabine was not antagonised by fl umazenil indicating interaction with other than benzodiazepine binding site s. In comparison with the K+ channel opening effect which can be seen at co ncentrations as low as 0.1 mu mol/l the contribution of this mechanism to t he anticonvulsant activity of retigabine may be minor. Inhibitory effects o bserved on voltage activated Na+ and Ca++ channels as well as on kainate in duced currents were only observed at the highest concentration tested (100 mu mol/l) and can be considered non specific. No significant interaction wi th NMDA induced currents was observed.