University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
Eur J Med Chem. 2013;70:154-64. doi: 10.1016/j.ejmech.2013.07.034. Epub 2013 Aug 11.
Clathrodin, alkaloid isolated from Agelas sponges, was reported in 1995 as a voltage-gated sodium channel modulator. Here we describe the design and synthesis of conformationally restricted clathrodin analogues incorporating the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine moiety and evaluation of their modulatory activities on human voltage-gated sodium channel isoforms Na(v)1.3, Na(v)1.4 and Na(v)1.7, as well as their selectivity against cardiac isoform Na(v)1.5. Compounds were shown to act as state-dependent modulators of Na(v)1.3, Na(v)1.4 and Na(v)1.7 with IC₅₀ values in the lower micromolar range for the open-inactivated state of the channels. Preliminary structure-activity relationship studies have revealed the importance of hydrophobic interactions for binding to all three tested isoforms. Compound 4e with IC₅₀ value of 8 μM against Na(v)1.4 represents a novel selective state-dependent Na(v)1.4 channel modulator.
克拉曲滨是一种从海绵 Agelas 中分离得到的生物碱，于 1995 年被报道为一种电压门控钠离子通道调节剂。在这里，我们描述了设计和合成具有受限构象的克拉曲滨类似物，其中包含 4,5,6,7-四氢苯并[d]噻唑-2-胺部分，并评估了它们对人电压门控钠离子通道亚型 Na(v)1.3、Na(v)1.4 和 Na(v)1.7 的调节活性，以及它们对心脏亚型 Na(v)1.5 的选择性。结果表明，这些化合物是钠离子通道的状态依赖性调节剂，对通道的开放失活状态的 IC₅₀ 值在较低的微摩尔范围内。初步的构效关系研究表明，疏水相互作用对于与所有三种测试的亚型结合很重要。化合物 4e 对 Na(v)1.4 的 IC₅₀ 值为 8 μM，代表了一种新型的选择性状态依赖性 Na(v)1.4 通道调节剂。
