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Molecular Pharmacology

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Research ArticleArticle

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

A. D. Wickenden, J. L. Krajewski, B. London, P. K. Wagoner, W. A. Wilson, S. Clark, R. Roeloffs, G. McNaughton-Smith and G. C. Rigdon
Molecular Pharmacology March 2008, 73 (3) 977-986; DOI: https://doi.org/10.1124/mol.107.043216
A. D. Wickenden
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J. L. Krajewski
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B. London
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P. K. Wagoner
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W. A. Wilson
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S. Clark
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R. Roeloffs
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G. McNaughton-Smith
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G. C. Rigdon
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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 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 (V½ 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 (ED50 = 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.

Footnotes

  • ABBREVIATIONS: AED, antiepileptic drug; ACSF, artificial cerebrospinal fluid; EGS, electrographic seizure; CNS, central nervous system; MES, maximal electroshock; CHO-K1, Chinese hamster ovary K1; DMSO, dimethyl sulfoxide; EBSS, Earle's balanced salt solution; HERG, human ether-a-go-go-related gene; XE-991, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received November 6, 2007.
    • Accepted December 17, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (3)
Molecular Pharmacology
Vol. 73, Issue 3
1 Mar 2008
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Research ArticleArticle

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

A. D. Wickenden, J. L. Krajewski, B. London, P. K. Wagoner, W. A. Wilson, S. Clark, R. Roeloffs, G. McNaughton-Smith and G. C. Rigdon
Molecular Pharmacology March 1, 2008, 73 (3) 977-986; DOI: https://doi.org/10.1124/mol.107.043216

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Research ArticleArticle

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

A. D. Wickenden, J. L. Krajewski, B. London, P. K. Wagoner, W. A. Wilson, S. Clark, R. Roeloffs, G. McNaughton-Smith and G. C. Rigdon
Molecular Pharmacology March 1, 2008, 73 (3) 977-986; DOI: https://doi.org/10.1124/mol.107.043216
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