ica-27243 and ezogabine

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

Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of K(v)7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of K(v)7 channels could be associated with changes in cerebral [¹⁴C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan K(v)7.2-K(v)7.5 channel opener) and ICA-27243 (K(v)7.2/K(v)7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both K(v)7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of K(v)7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric K(v)7.2/K(v)7.3 channels may present a novel anti-manic therapeutic target.

Topics: Animals; Antimanic Agents; Autoradiography; Benzamides; Bipolar Disorder; Carbamates; Central Nervous System Stimulants; Chlordiazepoxide; Deoxyglucose; Dextroamphetamine; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Hypnotics and Sedatives; KCNQ Potassium Channels; Male; Mice; Mice, Inbred C57BL; Phenylenediamines; Phosphorylation; Prefrontal Cortex; Pyridines; Serine

Kv7 channels, encoded by corresponding kcnq genes, are expressed both centrally and peripherally where they serve to dampen neuronal activity. While Kv7 channel openers have shown efficacy in neurological and neuropsychiatric disease models, the impact of Kv7 channel activation on physiological endpoint markers have not been addressed in detail. In this study we assessed the effect of a range of Kv7 channel openers with different affinity for neuronal Kv7.2-5 channel subunits on body temperature regulation in mice. Female NMRI mice were acutely exposed to vehicle (10% Tween-80, i.p.), retigabine (3-30 mg/kg, i.p., pan-Kv7 channel opener), (S)BMS-204352 (60-240 mg/kg, i.p., Kv7.4/5 channel-preferring opener), ICA-27243 (1-10mg/kg, i.p., Kv7.2/3 channel-preferring opener), or S-(1) (10-60 mg/kg, i.p., Kv7.2/3 channel-preferring opener), and rectal body temperature was measured 15-120 min post-injection. Retigabine (>10mg/kg), ICA-27243 (≥ 10 mg/kg), and S-(1) (≥ 30 mg/kg) dose-dependently lowered rectal body temperature with maximal doses of each Kv7 channel opener inducing a marked drop (>4°C) in rectal temperature. The Kv7 channel openers showed differential temporal pharmacodynamics, which likely reflects their different pharmacokinetic profiles. Pretreatment with the pan-Kv7 channel blocker XE-991 (1.0mg/kg, i.p.) completely reversed the hypothermic effect of the pan-Kv7 opener, retigabine (15 mg/kg), whereas ICA-27243-induced hypothermia (10mg/kg) could only be partially prevented by XE-991. Because ICA-27743 and S-(1) are Kv7.2/3 channel subunit-preferring compounds, this suggests that the Kv7.2/3 channel isoform is the predominant substrate for Kv7 channel opener-evoked hypothermia. These data indicate the physiological relevance of Kv7 channel function on body temperature regulation which may potentially reside from central inhibitory Kv7 channel activity.

Topics: Animals; Anthracenes; Anticonvulsants; Benzamides; Body Temperature Regulation; Carbamates; Female; Hypothermia; Indoles; KCNQ Potassium Channels; Mice; Phenylenediamines; Protein Isoforms; Pyridines

Retigabine is an anti-epileptic drug that inhibits neuronal firing by stabilizing the membrane potential through positive modulation of voltage-dependent KCNQ potassium channels in cortical neurons and in mesencephalic dopamine (DA) neurons. The purpose of this study was to compare the effect of retigabine with other positive KCNQ modulators on the KCl-induced release of DA in rat striatal slices. Retigabine was found to inhibit KCl-dependent release of DA, and the IC(50) was estimated to be 0.7 μM. The KCNQ channel blocker XE-991 enhanced striatal DA release and completely abolished the effect of retigabine. Other compounds of the same class but with some preferences for different KCNQ subtypes such as ICA-27243, BMS-204352 and S-(1) were also tested. All three compounds produced a significant effect albeit weaker than retigabine. The potency of ICA-27243 was in the range of retigabine, and with a lower potency of BMS-204352 and S-(1). This study demonstrates that KCNQ channel openers inhibit KCl-induced DA release at relevant concentrations. The equal potency of ICA-27243 and retigabine suggests that the KCNQ2/3 isoform is likely the dominant subtype mediating this effect.

Topics: Animals; Anthracenes; Anticonvulsants; Benzamides; Carbamates; Dopamine; Dopamine Antagonists; In Vitro Techniques; Indoles; Inhibitory Concentration 50; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Male; Mesencephalon; Neostriatum; Neurons; Nonlinear Dynamics; Phenylenediamines; Potassium Channel Blockers; Potassium Chloride; Pyridines; Rats; Rats, Wistar; Regression Analysis

the neuronal K(V)7 family members (K(V)7.2-5) are important regulators of neuronal excitability. K(V)7 channel openers are therefore attractive drug candidates for the treatment of several hyperexcitability disorders. While most described K(V)7 channel openers discriminate poorly between K(V)7.2-5, Icagen's N-(6-chloropyridin- 3-yl)-3,4-difluorobenzamide (ICA-27243) is more potent at K(V)7.2/3 than at K(V)7.4 and K(V)7.3/5 and offers some progress towards subtype selectivity. We have investigated its mode of action on K(V)7.2 and K(V)7.4, compared its effect to that of retigabine and studied the combinatorial effect of retigabine and ICA-27243, as these two compounds recognize different binding sites in the channels.. the effects of ICA-27243 and retigabine were studied using voltage-clamp electrophysiology in Xenopus laevis oocytes and rubidium flux in Chinese hamster ovary cells.. we found that in contrast to retigabine's voltage-dependent action on K(V)7.2, ICA-27243 induced a voltage-independent current on this subtype, which was not observed on K(V)7.4. Additionally, the combined treatment of K(V)7.2 and K(V)7.4 with retigabine and ICA-27243 revealed that the effect of ICA-27243 on K(V)7.2 dominates that of retigabine, while the compounds act additively and synergistically on K(V)7.4.. these results offer further detailed insight into pharmacological activation of K(V)7 channels and offer evidence of differential functional and subtype-specific effects by activation of different binding sites in the K(V)7 channels.

Topics: Animals; Benzamides; Binding Sites; Carbamates; Cells, Cultured; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Female; KCNQ Potassium Channels; KCNQ2 Potassium Channel; Membrane Potentials; Oocytes; Phenylenediamines; Pyridines; Rubidium Radioisotopes; Xenopus laevis

The mammalian KCNQ (Kv7) gene family is composed of five members (KCNQ1-5). KCNQ2, Q4 and Q5 (KCNQ2-5) channels co-express with KCNQ3 to form heterotetrameric voltage-gated K(+) (KCNQ2-5/3) channels that underlie the endogenous M-current and regulate neuronal excitability in CNS and PNS neurons. Openers of one or a mixture of these channels may be an attractive therapeutic agent for epilepsy and pain. Non-selective KCNQ2-5/3 activators have shown efficacy in pre-clinical and clinical studies. However, more selective pharmacological profiles, including greater KCNQ sub-type-selective activation, could provide efficacy with fewer side effects. One such compound, ICA-27243, sub-type selectively enhances the activation of KCNQ2/3 channels and also exhibits efficacy in pre-clinical anticonvulsant models; Roeloffs et al. (2008) [15]; Wickenden et al. (2008) [27]. The binding site of non-selective KCNQ2-5/3 openers maps to the S5-S6 pore domain and is altered by mutation of a tryptophan residue (Trp236 in KCNQ2, Trp265 in KCNQ3) conserved among KCNQ2-5 channels; Schenzer et al. (2005) [19]; Wuttke et al. (2005) [30]. Here we report that the activity of the KCNQ2/3 selective opener ICA-27243 is not affected by these Trp mutations and does not map to the S5-S6 domain. Rather, the selective activity of ICA-27243 is determined by a novel site within the S1-S4 voltage-sensor domain (VSD) of KCNQ channels. The sub-type-selective activity of ICA-27243 may arise from greater sequence diversity of KCNQ family members within the ICA-27243 binding pocket, allowing for more selective small molecule-protein interactions.

Topics: Amino Acid Sequence; Animals; Anticonvulsants; Benzamides; Binding Sites; Carbamates; CHO Cells; Cricetinae; Cricetulus; Humans; KCNQ Potassium Channels; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Membrane Potentials; Membrane Transport Modulators; Molecular Sequence Data; Mutation; Phenylenediamines; Pyridines; Sequence Alignment; Tryptophan

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