The therapeutic potential of neuronal KCNQ channel modulators.
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 trade mark 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.
Gribkoff
Valentin K
VK
Neuroscience Drug Discovery, Department 401, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Valentin.Gribkoff@bms.com
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000235:genetics; D011976:Receptors, Muscarinic / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000502:physiology; D014981:Xenopus
D018712:Analgesics, Non-Narcotic; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse; D009419:Nerve Tissue Proteins; D018697:Nootropic Agents; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011976:Receptors, Muscarinic; D011993:Recombinant Fusion Proteins; D011188:Potassium