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In vivo profile of ICA-27243 [N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide], a potent and selective KCNQ2/Q3 (Kv7.2/Kv7.3) activator in rodent anticonvulsant models.

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, ED(50) = 1.5 mg/kg p.o.; PTZ, ED(50) = 2.2 mg/kg p.o.) and mice (MES, ED(50) = 8.6 mg/kg p.o.; PTZ, ED(50) = 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 ED(50) = 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.
AuthorsRosemarie Roeloffs, Alan D Wickenden, Christopher Crean, Stephen Werness, Grant McNaughton-Smith, James Stables, James O McNamara, Neil Ghodadra, Greg C Rigdon
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 326 Issue 3 Pg. 818-28 (Sep 2008) ISSN: 1521-0103 [Electronic] United States
PMID18577704 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anticonvulsants
  • Benzamides
  • KCNQ2 Potassium Channel
  • KCNQ3 Potassium Channel
  • N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide
  • Pyridines
Topics
  • Animals
  • Anticonvulsants (pharmacology, therapeutic use)
  • Benzamides (pharmacology, therapeutic use)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • KCNQ2 Potassium Channel (agonists, metabolism)
  • KCNQ3 Potassium Channel (agonists, metabolism)
  • Male
  • Mice
  • Pyridines (pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Seizures (metabolism, prevention & control)

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