Retigabine dihydrochloride

Biological Activity

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. Retigabine is a novel anticonvulsant with an unknown mechanism of action. Application of 10 μM retigabine to oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activation threshold and voltage for half-activation by approximately 20 mV in the hyperpolarizing direction, leading to an increase in current amplitude at test potentials between ?80 mV and +20 mV. Retigabine also had a marked effect on KCNQ current kinetics, increasing the rate of channel activation but slowing deactivation at a given test potential. Retigabine shifted the voltage dependence of channel activation with an EC50value of 1.6 ± 0.3 μM (slope factor was 1.2 ± 0.1,n = 4 to 5 cells per concentration). Retigabine (0.1 to 10 μM) also slowed the rate of channel deactivation, predominantly by increasing the contribution of a slowly deactivating tail current component. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg) can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg). Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg), and this effect was reversed by XE991 (3 mg/kg). Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ. Retigabine exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model.

Published experimental findings depend on the model and assay conditions. They do not guarantee equivalent performance in every application. For laboratory research use only.