Department of Pharmacology, Qingdao University School of Pharmacy, Qingdao, China.
Department of Pharmacology, Peking University School of Pharmaceutical Sciences, Beijing, China.
Handb Exp Pharmacol. 2021;267:231-251. doi: 10.1007/164_2021_458.
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 In addition, flupirtine, a structural derivative of retigabine and a centrally acting non-opioid analgesic, was also withdrawn in 2018 for liver toxicity.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.
天然 M 电流是一种阈下、缓慢激活的钾电流，对神经元兴奋性具有抑制性控制作用。M 通道主要由异四聚体 Kv7.2/KCNQ2 和 Kv7.3/KCNQ3 亚基组成，这些亚基特异性表达于大脑和脊髓中外周伤害性和内脏感觉神经元。M 通道功能的降低导致神经元过度兴奋，这定义了癫痫和疼痛等神经紊乱的基本机制，表明 Kv7/KCNQ/M 通道的药理学激活可能为治疗提供基础。众所周知的 Kv7 开放剂瑞替加滨（依佐加滨或 Potiga）于 2011 年被 FDA 批准为抗惊厥药，用于部分癫痫的辅助治疗。不幸的是，由于长期服用后皮肤和眼睛呈蓝色的副作用，瑞替加滨于 2017 年被停用。此外，作为瑞替加滨的结构衍生物，具有中枢作用的非阿片类镇痛药氟吡汀也因肝毒性于 2018 年被撤回。幸运的是，这些副作用与化合物结构有关，可以避免。因此，进一步鉴定和开发新型有效且选择性 Kv7 通道开放剂可能为抗癫痫和抗伤害提供有效的治疗方法，并改善安全性。
