QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.137794v1 326/3/818    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roeloffs, R. Articles by Rigdon, G. C. Search for Related Content PubMed PubMed Citation Articles by Roeloffs, R. Articles by Rigdon, G. C.

NEUROPHARMACOLOGY

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

Icagen, Inc., Durham, North Carolina (R.R., A.D.W., C.C., S.W., G.M.-S., G.C.R.); Anticonvulsant Screening Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland (J.S.); and Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina (J.O.M., N.G.)

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.

Address correspondence to: Dr. Rosemarie Roeloffs, Icagen, Inc., 4222 Emperor Blvd., Suite 350, Durham, NC 27703. E-mail: rroeloffs{at}icagen.com