Cell-Based Assays Group, Millipore Corporation, St Charles, Missouri 63304, USA.
Expert Opin Investig Drugs. 2010 Jan;19(1):45-62. doi: 10.1517/13543780903435340.
Drugs inhibiting voltage-gated sodium channels have long been used as analgesics, beginning with the use of local anaesthetics for sensory blockade and then with the discovery that Nav-blocking anticonvulsants also have benefit for pain therapy. These drugs were discovered without knowledge of their molecular target, using traditional pharmacological methods, and their clinical utility is limited by relatively narrow therapeutic windows. Until recently, attempts to develop improved inhibitors using modern molecular-targeted screening approaches have met with limited success. However, in the last few years there has been renewed activity following the discovery of human Nav1.7 mutations that cause striking insensitivity to pain. Together with recent advances in the technologies required to prosecute ion channels as drug targets, this has led to significant progress being made. This article reviews these developments and summarises current findings with these emerging new Nav inhibitors, highlighting some of the unanswered questions and the challenges that remain before they can be developed for clinical use.
电压门控钠离子通道抑制剂长期以来一直被用作镇痛药，最早是使用局部麻醉剂进行感觉阻断，然后发现 Nav 阻断抗惊厥药对疼痛治疗也有好处。这些药物是在不知道其分子靶点的情况下，使用传统的药理学方法发现的，其临床应用受到相对较窄的治疗窗口的限制。直到最近，使用现代分子靶向筛选方法开发改良抑制剂的尝试才取得了有限的成功。然而，在发现导致对疼痛明显不敏感的人类 Nav1.7 突变后，最近几年又重新活跃起来。再加上进行离子通道作为药物靶点研究所需的技术的最新进展，这使得取得了重大进展。本文综述了这些进展，并总结了目前这些新兴的 Nav 抑制剂的研究结果，突出了一些尚未解决的问题和在将它们开发用于临床应用之前仍然存在的挑战。
