Electrophysiological and Pharmacological Characterization of a Novel and Potent Neuronal Kv7 Opener SCR2682 for Anti-Epilepsy

Abstract

Voltage-gated Kv7/KCNQ/M-potassium channels play an essential role in control of membrane potential and neuronal excitability. Activation of neuronal Kv7/KCNQ/M-current represents an attractive therapeutic strategy for treatment of hyperexcitability-related neuropsychiatric disorders such as epilepsy, pain and schizophrenia. In this study, we synthesized and characterized a novel series of 2,6-dimethyl-4-(piperidin-yl)phenyl)-amide derivatives that exhibit selective and potent activation of neuronal Kv7/KCNQ/M channels. Whole-cell patch clamp recordings of HEK293 cells expressing Kv7.2/Kv7.3 channels show that a representative compound SCR2682 selectively activates the channel current in dose-dependent manner with an EC50 of 9.8 ± 0.4 nM, which is about 100-fold potent than antiepileptic drug retigabine approved by FDA for partial epilepsy. Compound SCR2682 shifts the voltage-dependent activation of Kv7.2/7.3 current towards more negative membrane potential about −37 mV (V1/2). SCR2682 also activates native M current of rat hippocampal or cortical neurons, causing a marked hyperpolarization and potent inhibition of evoked action potentials. In rat epileptic models, intraperitoneal and intragastric administrations of SCR2682 results in a dose-dependent inhibition of seizures. Taken together, our findings demonstrate that a novel SCR2682 selectively and potently activates neuronal Kv7 channels and reverses epileptic activity in rats. Thus, SCR2682 may warrant further evaluation for clinical development of antiepileptic therapy.