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首页> 外文期刊>CNS drug reviews >Retigabine: chemical synthesis to clinical application.
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Retigabine: chemical synthesis to clinical application.

机译：瑞替加滨：化学合成到临床应用。

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Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
机译：瑞替加滨[D23129; N-（2-氨基-4-（4-氟苄氨基）-苯基）氨基甲酸乙酯]是一种抗癫痫药，具有最近描述的新作用机制，涉及打开神经元K（V）7.2-7.5（以前称为KCNQ2- 5）电压激活的K（+）通道。这些通道（主要是K（V）7.2 / 7.3）可产生M电流，即一个亚阈值K（+）电流，用于稳定膜电位并控制神经元兴奋性。在这方面，已证明瑞替加滨在电诱发的（杏仁核种，最大的电击）和化学诱发的（戊四氮，pictotoxin，NMDA）癫痫发作的动物模型中具有广谱的活性。这些令人鼓舞的结果表明，瑞替加滨还可用于治疗与神经元过度兴奋有关的其他疾病。神经性疼痛状况的特征在于感觉途径的病理变化，这有利于动作电位的产生和疼痛传递的增强。尽管有时用常规镇痛药很难治疗，但抗癫痫药可以缓解神经性疼痛的某些症状。最近的许多研究报告说，在神经性疼痛的动物模型中，瑞替加滨可以缓解疼痛样行为（痛觉过敏和异常性疼痛）。在各种焦虑症动物模型中，也可以观察到CNS几个关键结构内的神经元激活。此外，杏仁核种的大鼠神经元活化的阈值降低，也表现出增强的焦虑样反应。当在小鼠大理石掩埋试验和零迷宫中评估时，瑞替加滨剂量依赖性地减少了无条件的焦虑样行为。早期的临床研究表明，瑞替加滨被迅速吸收和分布，并且对首过代谢具有抵抗力。当滴定至其治疗剂量范围（600-1200 mg / day）时，人类的耐受性良好。尽管不良反应可能包括轻度头晕，头痛，恶心和嗜睡，但尚无耐受，依赖性或戒断潜力的报道。因此，瑞替加滨可能被证明可用于治疗多种疾病状态，其中神经元过度兴奋是常见的潜在因素。

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