The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential

BACKGROUND AND PURPOSE: KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential. EXPERIMENTAL APPROACH: The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from Chinese hamster ovary cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro. KEY RESULTS: 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarising shift of the activation curve and a pronounced slowing of deactivation in KCNQ2 mediated currents whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine insensitive mutant KCNQ2-W236L. In fully amygdala kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarisation and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of gamma and theta oscillation peak power with no significant change in oscillation frequency. CONCLUSION AND IMPLICATIONS: Our data indicates that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo.