ica-27243 and Disease-Models--Animal

Refractory chronic pain dramatically reduces the quality of life of patients. Existing drugs cannot fully achieve effective chronic pain control because of their lower efficacy and/or accompanying side effects. Voltage-gated potassium channels (KCNQ) openers have demonstrated their analgesic effect in preclinical and clinical studies, and are thus considered to be a potential therapeutic target as analgesics. However, these drugs exhibit a narrow therapeutic window due to their imposed central nerve system (CNS) side effects. To clarify the analgesic effect by peripheral KCNQ channel activation, we investigated whether the analgesic effect of the KCNQ channel opener, retigabine, is inhibited by intracerebroventricular (i.c.v.) administration of the KCNQ channel blocker, 10, 10-bis (4-Pyridinylmethyl)-9(10H) -anthracenone dihydrochloride (XE-991) in rats.. Oral administration (p.o.) of retigabine showed an anticonvulsant effect on maximal electronic seizures and an analgesic effect on complete Freund's adjuvant-induced thermal hyperalgesia. However, impaired motor coordination and reduced exploratory behavior were also observed at the analgesic doses of retigabine. Administration (i.c.v.) of XE-991 reversed the retigabine-induced anticonvulsant effect, impaired motor coordination and reduced exploratory behavior but not the analgesic effect. Moreover, intraplantar administration of retigabine or an additional KCNQ channel opener, N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243), inhibited formalin-induced nociceptive behavior.. Our findings suggest that the peripheral sensory neuron is the main target for KCNQ channel openers to induce analgesia. Therefore, peripheral KCNQ channel openers that do not penetrate the CNS may be suitable analgesic drugs as they would prevent CNS side effects.

Topics: Animals; Anthracenes; Anticonvulsants; Benzamides; Carbamates; Disease Models, Animal; Electric Stimulation; Exploratory Behavior; Formaldehyde; Freund's Adjuvant; Functional Laterality; Hyperalgesia; Inflammation; KCNQ Potassium Channels; Motor Skills Disorders; Pain; Pain Measurement; Pain Threshold; Phenylenediamines; Potassium Channel Blockers; Pyridines; Rats

In an effort to investigate the potential antimanic-like activity of K(v)7 channel openers, we decided to test: (1) the subtype non-selective K(v)7 opener retigabine, (2) the K(v)7.4-K(v)7.5 (and K(v)7.5/3 heteromers) preferring channel opener BMS-204352 (Maxipost), and (3) the novel K(v)7.2/3 preferring channel opener ICA-27243, in the amphetamine (AMPH)+chlordiazepoxide (CDP)-induced hyperactivity paradigm in mice, a test often used to assess potential antimanic-like activity of novel compounds. Lithium and lamotrigine were included as positive controls. Pretreatment with lithium attenuated AMPH/CDP-induced hyperactivity, without affecting the activity of AMPH- or CDP-alone, and thus confirmed some predictive validity for the test paradigm. Pretreatment with lamotrigine significantly attenuated AMPH/CDP-induced effects, but also reduced motility when tested in the presence of CDP-alone. Pretreatment with retigabine or ICA-27243 attenuated AMPH/CDP-induced hyperactivity without affecting basal locomotor activity. In contrast, pretreatment with BMS-204352 failed to decrease AMPH/CDP-induced hyperactivity at lower doses (3 and 10 mg/kg). At higher doses BMS-204352 attenuated hyperactivity induced by the AMPH/CDP mix, but only at doses decreasing basal locomotor activity (30 and 60 mg/kg). None of the K(v)7 openers tested significantly affected AMPH-induced hyperactivity. In contrast, retigabine and ICA-27243 were shown to induce significant reductions in motility when administered in combination with CDP-alone. In conclusion, the results with lithium confirm some predictive validity for the test paradigm. However, our data highlight an important confounder for interpreting a role for K(v)7 channels in the alleviation of manic-like symptoms when employing the AMPH/CDP hyperactivity model in mice. It is imperative that relevant control studies (AMPH- and CDP-alone) be incorporated and reported routinely to enable thorough interpretation of data generated by means of this behavioural test.

Topics: Amphetamine; Animals; Anticonvulsants; Antimanic Agents; Benzamides; Bipolar Disorder; Carbamates; Central Nervous System Stimulants; Chlordiazepoxide; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hyperkinesis; Indoles; Injections, Intraperitoneal; KCNQ Potassium Channels; Lamotrigine; Lithium Compounds; Male; Mice; Mice, Inbred C57BL; Motor Activity; Phenylenediamines; Pyridines; Triazines

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.

Topics: Animals; Anticonvulsants; Benzamides; Disease Models, Animal; Dose-Response Relationship, Drug; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Male; Mice; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Seizures