Pharmacological Activation of Neuronal Voltage-Gated Kv7/KCNQ/M-Channels for Potential Therapy of Epilepsy and Pain

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Abstract
Native M-current is a low-threshold, slowly activating potassium current that exerts an inhibitory control over neuronal excitability. The M-channel is primarily co-assembled by heterotetrameric Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits that are specifically expressed in the brain and peripheral nociceptive and visceral sensory neurons in the spinal cord. Reduction of M-channel function leads to neuronal hyperexcitability that defines the fundamental mechanism of neurological disorders such as epilepsy and pain, indicating that pharmacological activation of Kv7/KCNQ/M-channels may serve the basis for the therapy. The well-known KCNQ opener retigabine (ezogabine or Potiga) was approved by FDA in 2011 as an anticonvulsant used for an adjunctive treatment of partial epilepsies. Unfortunately, retigabine was discontinued in 2017 due to its side effects of blue-colored appearance of the skin and eyes after prolonged intake. In addition, flupirtine, a structural derivative of retigabine and a centrally acting non-opioid analgesic, was also withdrawn in 2018 for liver toxicity. Fortunately, these side effects are compound-structures related and can be avoided. Thus, further identification and development of novel potent and selective Kv7 channel openers may lead to an effective therapy with improved safety window for anti-epilepsy and anti-nociception.

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