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 ϭ 1.5 mg/kg p.o.; PTZ, ED 50 ϭ 2.2 mg/kg p.o.) and mice (MES, ED 50 ϭ 8.6 mg/kg p.o.; PTZ, ED 50 ϭ 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 ϭ 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.KCNQ2-5 (Kv7.2-7.5) voltage-dependent potassium channels are potentially attractive targets for novel antiepileptic drugs. These channels are expressed at high levels in the brain, including regions linked to seizure disorders, such as cortex, hippocampus, and thalamus. They represent the molecular correlate of the neuronal M current

Isoform-specific Prolongation of Kv7 (KCNQ) Potassium Channel Opening Mediated by New Molecular Determinants for Drug-Channel Interactions

“…Hence, the two modes of potentiation, hypopolariz- ing shift of V1 ⁄ 2 and slowing of deactivation, appear to be contributed by different groups on the compounds. ztz233 is, in fact, identical to the structure of ICA-27243, which has been reported for its potent effects on both recombinant KCNQ2/3 channels and anti-epileptic activities (12,14). The EC 50 values for KCNQ2/3 were 5.7 Ϯ 0.6 M for ztz233 and 6.1 Ϯ 1.2 M for ztz240.…”

“…3), arguing that the in vivo activity of ICA-27243 reported earlier is due to its effects on KCNQ channels (12). The effects Fig.…”

“…These structures displayed considerable similarity to an ICAgen compound, ICA-27243 ( Fig. 1C) (11)(12)(13)(14). To explore this notion, we first examined a series of analogues with different nitrogen positions.…”

“…For example, potent anti-epileptic activities were reported for ICA-27243 in various rodent convulsant models (e.g. ED 50 values were 1.5 and 2.2 mg/kg per oral for maximal electroshock-and pentylenetetrazole-induced seizure models in rats, respectively) (11)(12)(13)(14). However, for most of these compounds, limited structure-activity relationship (SAR) 6 data are available.…”

Anticonvulsant profile of 2-ethylthio-7-methyl-4-(4-methylphenyl)pyrazolo[1,5-a][1,3,5]triazine

“…The latency period until seizure induced by pentilenetetrazol is considered in a similar fashion (Roeloffs et al, 2008). However, the predictive value of a potential anticonvulsant only considering the capacity to prevent the seizure could be a better parameter, because the anticonvulsant should not only be able to decrease the length of time of an experimental seizure but also prevent it.…”