Document Detail

Modulation of K(v)7 potassium channels by a novel opener pyrazolo[1,5-a]pyrimidin-7(4H)-one compound QO-58.
MedLine Citation:
PMID:  23013484     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: 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.
EXPERIMENTAL APPROACH: 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.
KEY 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 AND IMPLICATIONS: 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.
F Zhang; Y Mi; J L Qi; J W Li; M Si; B C Guan; X N Du; H L An; H L Zhang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-25     Completed Date:  2013-07-16     Revised Date:  2014-02-04    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1030-42     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Action Potentials / drug effects
CHO Cells
Dose-Response Relationship, Drug
Ion Channel Gating / drug effects*
KCNQ2 Potassium Channel / genetics,  metabolism*
KCNQ3 Potassium Channel / genetics,  metabolism*
Molecular Structure
Neuralgia / drug therapy,  metabolism
Neurons / drug effects,  metabolism
Patch-Clamp Techniques
Pyrazoles / chemistry,  pharmacology*,  therapeutic use
Pyrimidines / chemistry,  pharmacology*,  therapeutic use
Pyrimidinones / chemistry,  pharmacology*,  therapeutic use
Rats, Sprague-Dawley
Structure-Activity Relationship
Reg. No./Substance:
0/KCNQ2 Potassium Channel; 0/KCNQ3 Potassium Channel; 0/Pyrazoles; 0/Pyrimidines; 0/Pyrimidinones; 0/QO-58 ion channel modulator; 0/pyrazolo(1,5-a)pyrimidine

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