Zuliani Valentina, Patel Manoj K, Fantini Marco, Rivara Mirko
Dipartimento Farmaceutico, Universitá degli Studi di Parma, V.le G.P. Usberti, 27/A, I-43100 Parma, Italy.
Curr Top Med Chem. 2009;9(4):396-415. doi: 10.2174/156802609788317856.
The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability. Abnormal activity of sodium channels is related to several pathological processes, including cardiac arrhythmias, epilepsy, chronic pain, neurodegenerative diseases and spasticity. In view of this, VGSCs are considered important therapeutic targets for the treatment of these disorders. To date, nine VGSC isoforms have been identified and have a distinct pattern of expression within the human body. In addition, VGSCs also have distinct electrophysiological profiles with differing activation and inactivation states. As such, there is a concerted effort to develop not only isoform selective antagonists, but also antagonists that exhibit state selectivity, particularly to the inactivated state of the channel. This review will provide a brief historical prospective and will primarily focus on recent advances in the development of isoform specific and state selective sodium channel antagonists and the medicinal chemistry involved, surveying the emerging therapeutic fields.
电压门控钠通道（VGSCs）在控制细胞兴奋性方面发挥着重要作用。钠通道的异常活动与多种病理过程相关，包括心律失常、癫痫、慢性疼痛、神经退行性疾病和痉挛。鉴于此，电压门控钠通道被认为是治疗这些疾病的重要治疗靶点。迄今为止，已鉴定出九种电压门控钠通道亚型，它们在人体内具有独特的表达模式。此外，电压门控钠通道还具有不同的电生理特性，其激活和失活状态各异。因此，人们不仅致力于开发亚型选择性拮抗剂，还致力于开发具有状态选择性的拮抗剂，特别是对通道失活状态具有选择性的拮抗剂。本综述将提供一个简要的历史展望，并将主要关注亚型特异性和状态选择性钠通道拮抗剂开发的最新进展以及所涉及的药物化学，探讨新兴的治疗领域。
