The therapeutic potential of neuronal KCNQ channel modulators

Abstract

Neuronal KCNQ (Kv7) channels (KCNQ2 – 5 or Kv7.2 – 7.5, disclosed to date) were discovered by virtue of their homology with a known cardiac channel involved in long QT syndrome (KvLQT or KCNQ1, Kv7.1) and first disclosed in 1998. The involvement of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) in a benign idiopathic neonatal epilepsy, KCNQ4 (Kv7.4) in a form of congenital deafness, and the discovery that neuronal KCNQ heteromultimers were among the molecular substrates of M-channels, resulted in a high level of interest for potential drug development strategies. A number of small-molecule modulators were quickly identified, including openers or activators such as the antiepileptic drug candidate retigabine and the structurally-related analgesic drug flupirtine (Katadolon™ Asta Medica), and a group of KCNQ channel inhibitors/blockers originally developed for cognition enhancement. All of these data have suggested a rich target profile for modulators of neuronal KCNQ channels, including a variety of neuronal hyperexcitability disorders and conditions for openers, such as the epilepsies, acute pain, neuropathic pain, migraine pain and some neurodegenerative and psychiatric disorders. KCNQ blockers could likewise have utility in disorders characterised by neuronal hypoactivity, including cognition enhancement and perhaps disorders of mood. Emerging patent literature suggests significant interest in neuronal KCNQ modulation in the pharmaceutical industry and significant chemical diversity concerning KCNQ modulation.