Received for publication November 9, 2007.
Revised December 14, 2007.
Accepted for publication December 17, 2007.

ICA-27243: A novel, selective KCNQ2/Q3 potassium channel activator

Abstract

KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) are voltage-gated K⁺ channel subunits that underlie the neuronal M-current. In humans, mutations in these genes lead to a rare form of neonatal epilepsy (Singh et al., 1998; Biervert et al., 1998), suggesting that KCNQ2/Q3 channels may be attractive targets for novel anti-epileptic drugs. In the present study we have identified the compound ICA-27243, (N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide) as a selective activator of the neuronal M-current and KCNQ2/Q3 channels. In SH-SY5Y human neuroblastoma cells, ICA-27243 produced membrane potential hyperpolarization that could be prevented by coadministration with the M-current inhibitors XE-911 and linopirdine. ICA-27243 enhanced both ⁸⁶Rb⁺ efflux (EC₅₀ = 0.2 µM) and whole-cell currents in Chinese Hamster Ovary cells stably expressing heteromultimeric KCNQ2/Q3 channels (EC₅₀ =0.4 µM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation (V_1/2 shift of -19 mV at 10 µM). In contrast, ICA-27243 was less effective at activating KCNQ4 and KCNQ3/Q5, and was selective over a wide range of neurotransmitter receptors and ion channels such as voltage dependent sodium channels and GABA-gated chloride channels. ICA-27243 (1-10µM) was found to reversibly suppress seizure-like activity in an ex vivo hippocampal slice model of epilepsy, and demonstrated in vivo anti-convulsant activity (ED₅₀ of 8.4 mg/kg) in the mouse maximal electroshock (MES) epilepsy model. In conclusion, ICA-27243 represents the first member of a novel chemical class of selective KCNQ2/Q3 activators with anticonvulsant-like activity in experimental models of epilepsy.

Key words: Ion channel regulation, Excitotoxicity, neurodegeneration

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