title: Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58.
abstract: OBJECTIVE
  Modulation of K(v)7/M channel function represents a relatively new strategy to treat neuronal excitability disorders such as epilepsy and neuropathic pain. We designed and synthesized a novel series of pyrazolo[1,5-a] pyrimidin-7(4H)-one compounds, which activate K(v)7 channels. Here, we characterized the effects of the lead compound, QO-58, on K(v)7 channels and investigated its mechanism of action.
  
  
  METHODS
  A perforated whole-cell patch technique was used to record K(v)7 currents expressed in mammalian cell lines and M-type currents from rat dorsal root ganglion neurons. The effects of QO-58 in a rat model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve, were also examined.
  
  
  RESULTS
  QO-58 increased the current amplitudes, shifted the voltage-dependent activation curve in a more negative direction and slowed the deactivation of K(v)7.2/K(v)7.3 currents. QO-58 activated K(v)7.1, K(v)7.2, K(v)7.4 and K(v)7.3/K(v)7.5 channels with a more selective effect on K(v)7.2 and K(v)7.4, but little effect on K(v)7.3. The mechanism of QO-58's activation of K(v)7 channels was clearly distinct from that used by retigabine. A chain of amino acids, Val(224)Val(225)Tyr(226), in K(v)7.2 was important for QO-58 activation of this channel. QO-58 enhanced native neuronal M currents, resulting in depression of evoked action potentials. QO-58 also elevated the pain threshold of neuropathic pain in the sciatic nerve CCI model.
  
  
  CONCLUSIONS
  The results indicate that QO-58 is a potent modulator of K(v)7 channels with a mechanism of action different from those of known K(v)7 openers. Hence, QO-58 shows potential as a treatment for diseases associated with neuronal hyperexcitability.
authors.affiliation: The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, China. zhangfanyaoli@yahoo.com.cn
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Mi
authors.forename: J L
authors.initials: JL
authors.lastname: Qi
authors.forename: J W
authors.initials: JW
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Si
authors.forename: B C
authors.initials: BC
authors.lastname: Guan
authors.forename: X N
authors.initials: XN
authors.lastname: Du
authors.forename: H L
authors.initials: HL
authors.lastname: An
authors.forename: H L
authors.initials: HL
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D051658:KCNQ2 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; C582146:QO-58 ion channel modulator; C527752:pyrazolo(1,5-a)pyrimidine