title: Differential effects of ICA-27243 on cloned K(V)7 channels.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Section of Early Target Pharmacology and Physiology, H. Lundbeck A/S, Valby, Denmark.
authors: Sigrid Marie
authors: SM
authors: Blom
authors: Nicole
authors: N
authors: Schmitt
authors: Henrik Sindal
authors: HS
authors: Jensen
mesh_terms: D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D016466:CHO Cells; D002219:Carbamates / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D051656:KCNQ Potassium Channels / Q000378:metabolism*; D051658:KCNQ2 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D010655:Phenylenediamines / Q000378:metabolism / Q000494:pharmacology; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D012414:Rubidium Radioisotopes / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D001549:Benzamides; D002219:Carbamates; D051656:KCNQ Potassium Channels; D051658:KCNQ2 Potassium Channel; C117367:KCNQ4 protein, human; C527835:N-(6-Chloropyridin-3-yl)-3,4-difluorobenzamide; D010655:Phenylenediamines; D011725:Pyridines; D012414:Rubidium Radioisotopes; C101866:ezogabine