title: 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.
authors.affiliation: Icagen, Inc., 4222 Emperor Blvd., Suite 350, Durham, NC 27703, USA. rroeloffs@icagen.com
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Roeloffs
authors.forename: Alan D
authors.initials: AD
authors.lastname: Wickenden
authors.forename: Christopher
authors.initials: C
authors.lastname: Crean
authors.forename: Stephen
authors.initials: S
authors.lastname: Werness
authors.forename: Grant
authors.initials: G
authors.lastname: McNaughton-Smith
authors.forename: James
authors.initials: J
authors.lastname: Stables
authors.forename: James O
authors.initials: JO
authors.lastname: McNamara
authors.forename: Neil
authors.initials: N
authors.lastname: Ghodadra
authors.forename: Greg C
authors.initials: GC
authors.lastname: Rigdon
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D051658:KCNQ2 Potassium Channel / Q000819:agonists* / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000819:agonists* / Q000378:metabolism; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012640:Seizures / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000927:Anticonvulsants; D001549:Benzamides; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D011725:Pyridines