Gribkoff Valentin K
Neuroscience Drug Discovery, Department 401, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA.
Expert Opin Ther Targets. 2003 Dec;7(6):737-48. doi: 10.1517/14728222.7.6.737.
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.
神经元KCNQ（Kv7）通道（迄今已披露的KCNQ2 - 5或Kv7.2 - 7.5）是因其与一种已知的参与长QT综合征的心脏通道（KvLQT或KCNQ1，Kv7.1）具有同源性而被发现的，并于1998年首次披露。KCNQ2（Kv7.2）和KCNQ3（Kv7.3）与一种良性特发性新生儿癫痫有关，KCNQ4（Kv7.4）与一种先天性耳聋形式有关，并且发现神经元KCNQ异源多聚体是M通道的分子底物之一，这引发了对潜在药物开发策略的高度关注。很快就鉴定出了许多小分子调节剂，包括开放剂或激活剂，如抗癫痫药物候选物瑞替加滨以及结构相关的镇痛药氟吡汀（商品名Katadolon，阿斯泰制药公司），还有一组最初为增强认知而开发的KCNQ通道抑制剂/阻滞剂。所有这些数据都表明，神经元KCNQ通道调节剂具有丰富的靶点特征，包括多种神经元兴奋性过高疾病，对于开放剂而言还有一些疾病状况，如癫痫、急性疼痛、神经性疼痛、偏头痛疼痛以及一些神经退行性和精神疾病。KCNQ阻滞剂同样可能对以神经元活性低下为特征的疾病有用，包括增强认知以及或许对情绪障碍也有用。新兴的专利文献表明，制药行业对神经元KCNQ调节有浓厚兴趣，并且在KCNQ调节方面存在显著的化学多样性。
