N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (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 (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(10H)-anthracenone dihydrochloride (XE-991) and linopirdine. ICA-27243 enhanced both (86)Rb(+) efflux (EC(50) = 0.2 microM) and whole-cell currents in Chinese hamster ovary cells stably expressing heteromultimeric KCNQ2/Q3 channels (EC(50) = 0.4 microM). 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 microM). 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 microM) 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.

• Authors: A D Wickenden, J L Krajewski, B London, P K Wagoner, W A Wilson, S Clark, R Roeloffs, G McNaughton-Smith, G C Rigdon
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 73 Issue 3 Pg. 977-86 (Mar 2008) ISSN: 1521-0111 [Electronic] United States
• PMID: 18089837 (Publication Type: Journal Article)

Chemical References

• Benzamides
• KCNQ2 Potassium Channel
• KCNQ3 Potassium Channel
• N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide
• Pyridines
• RNA, Messenger

Topics

• Animals
• Benzamides (pharmacology)
• CHO Cells
• Cell Culture Techniques
• Cell Line
• Cell Line, Tumor
• 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)
• RNA, Messenger (analysis)
• Rats
• Rats, Sprague-Dawley
• Sensitivity and Specificity