Premium
Modulation of K v 7 potassium channels by a novel opener pyrazolo[1,5‐a]pyrimidin‐7( 4H )‐one compound QO ‐58
Author(s) -
Zhang F,
Mi Y,
Qi JL,
Li JW,
Si M,
Guan BC,
Du XN,
An HL,
Zhang HL
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02232.x
Subject(s) - dorsal root ganglion , sciatic nerve , neuropathic pain , potassium channel , stereochemistry , chemistry , biophysics , neuroscience , dorsum , anatomy , medicine , biology
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.