Abstract
Openers or activators of neuronal KCNQ2/Q3 potassium channels decrease neuronal excitability and may provide benefit in the treatment of disorders of neuronal excitability such as epilepsy. In the present study, we evaluate the effects of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide], an orally bioavailable, potent, and selective KCNQ2/Q3 opener, in a broad range of rodent seizure models. ICA-27243 was effective against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced seizures in both rats (MES, ED50 = 1.5 mg/kg p.o.; PTZ, ED50 = 2.2 mg/kg p.o.) and mice (MES, ED50 = 8.6 mg/kg p.o.; PTZ, ED50 = 3.9 mg/kg p.o.) in the rat amygdala kindling model of partial seizures (full protection from seizure at 9 mg/kg p.o.) and in the 6-Hz model of psychomotor seizures in mice (active at 10 mg/kg i.p.). Antiseizure efficacy in all models was observed at doses significantly less than those shown to effect open-field locomotor activity (rat ED50 = 40 mg/kg p.o.) or ability to remain on a Rotorod (no effect in rat at doses up to 100 mg/kg p.o.). There was no evidence of cognition impairment as measured in the Morris water maze in the rat (10 and 30 mg/kg p.o.), nor was there evidence of the development of tolerance after multiple doses of ICA-27243. Our findings suggest that selective KCNQ2/Q3 opening activity in the absence of effects on KCNQ3/Q5 or GABA-activated channels may be sufficient for broad-spectrum antiepileptic activity in rodents.
Footnotes
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R.R., S.W., and G.C.R. are employees of Icagen, Inc. and are owners of Icagen stock and Icagen stock options. A.D.W., G.M.-S., and C.C. are former Icagen employees who received Icagen stock option grants as part of their compensation. Rat amygdala kindling studies were conducted in the laboratory of J.O.M. by N.G. (Duke University Medical School, Durham, NC), and these studies were supported by a grant from Icagen. In addition, J.O.M. declares that he has served as an advisor to Icagen, that his compensation has included options for shares in Icagen, and that he currently owns shares in the company.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.137794.
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ABBREVIATIONS: KCNQ2/Q3, Kv7.2/Kv7.3; D-23129, N-(2-amino-4-[fluorobenzylamino]-phenyl) carbamic acid; ICA-27243, N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide; KCNQ4, Kv7.4; KCNQ3/Q5, Kv7.3/Kv7.5; MES, maximal electroshock; PTZ, pentylenetetrazole; AD, afterdischarge; GST, generalized seizure threshold; ADD, afterdischarge duration; ANOVA, analysis of variance; CI, confidence interval; ABT-769, (R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide; XE911, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride.
- Received February 7, 2008.
- Accepted June 23, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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