title: The new KCNQ2 activator 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid displays anticonvulsant potential.
abstract: OBJECTIVE
  KCNQ2-5 channels are voltage-gated potassium channels that regulate neuronal excitability and represent suitable targets for the treatment of hyperexcitability disorders. The effect of Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was tested on KCNQ subtypes for its ability to alter neuronal excitability and for its anticonvulsant potential.
  
  
  METHODS
  The effect of 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid was evaluated using whole-cell voltage-clamp recordings from CHO cells and Xenopus laevis oocytes expressing different types of KCNQ channels. Epileptiform afterdischarges were recorded in fully amygdala-kindled rats in vivo. Neuronal excitability was assessed using field potential and whole cell recording in rat hippocampus in vitro.
  
  
  RESULTS
  4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a hyperpolarizing shift of the activation curve and a pronounced slowing of deactivation in KCNQ2-mediated currents, whereas KCNQ3/5 heteromers remained unaffected. The effect was also apparent in the Retigabine-insensitive mutant KCNQ2-W236L. In fully amygdala-kindled rats, it elevated the threshold for induction of afterdischarges and reduced seizure severity and duration. In hippocampal CA1 cells, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid strongly damped neuronal excitability caused by a membrane hyperpolarization and a decrease in membrane resistance and induced an increase of the somatic resonance frequency on the single cell level, whereas synaptic transmission was unaffected. On the network level, 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid caused a significant reduction of γ and θ oscillation peak power, with no significant change in oscillation frequency.
  
  
  CONCLUSIONS
  Our data indicate that 4-Chlor-N-(6-chlor-pyridin-3-yl)-benzamid is a potent KCNQ activator with a selectivity for KCNQ2 containing channels. It strongly reduces neuronal excitability and displays anticonvulsant activity in vivo.
authors.affiliation: Institute of Neurophysiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Boehlen
authors.forename: M
authors.initials: M
authors.lastname: Schwake
authors.forename: R
authors.initials: R
authors.lastname: Dost
authors.forename: A
authors.initials: A
authors.lastname: Kunert
authors.forename: P
authors.initials: P
authors.lastname: Fidzinski
authors.forename: U
authors.initials: U
authors.lastname: Heinemann
authors.forename: C
authors.initials: C
authors.lastname: Gebhardt
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D066298:In Vitro Techniques; D051658:KCNQ2 Potassium Channel / Q000819:agonists* / Q000502:physiology; D009865:Oocytes; D010655:Phenylenediamines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects; D014982:Xenopus laevis
chemical_list: C582778:4-chloro-N-(6-chloropyridin-3-yl)benzamide; D000927:Anticonvulsants; D001549:Benzamides; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D010655:Phenylenediamines; D011725:Pyridines; C101866:ezogabine