N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): A Novel, Selective KCNQ2/Q3 Potassium Channel Activator

• Published in: Molecular pharmacology Vol. 73; no. 3; pp. 977 - 986
• Main Authors: Wickenden, A D, Krajewski, J L, London, B, Wagoner, P K, Wilson, W A, Clark, S, Roeloffs, R, McNaughton-Smith, G, Rigdon, G C
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.03.2008
• Subjects: Animals; Benzamides - pharmacology; Cell Culture Techniques; Cell Line; Cell Line, Tumor; CHO Cells; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrophysiology; Hippocampus - metabolism; Humans; Inhibitory Concentration 50; KCNQ2 Potassium Channel - drug effects; KCNQ3 Potassium Channel - drug effects; Kidney - cytology; Male; Membrane Potentials - drug effects; Microelectrodes; Neuroblastoma - pathology; Patch-Clamp Techniques; Plasmids; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Messenger - analysis; Sensitivity and Specificity
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.107.043216

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 ( Biervert et al., 1998 ; Singh et al., 1998 ), suggesting that KCNQ2/Q3 channels may be attractive targets for novel antiepileptic drugs. In the present study, we have identified the compound N -(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243) 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 10,10-bis(4-pyridinylmethyl)-9(10 H )-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both 86 Rb + efflux (EC 50 = 0.2 μM) and whole-cell currents in Chinese hamster ovary cells stably expressing heteromultimeric KCNQ2/Q3 channels (EC 50 = 0.4 μM). Activation of KCNQ2/Q3 channels was associated with a hyperpolarizing shift of the voltage dependence of channel activation ( V ½ 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 (1-10 μM) was found to reversibly suppress seizure-like activity in an ex vivo hippocampal slice model of epilepsy and demonstrated in vivo anticonvulsant activity (ED 50 = 8.4 mg/kg) in the mouse maximal electroshock 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.