Wulff H, Rauer H, Düring T, Hanselmann C, Ruff K, Wrisch A, Grissmer S, Hänsel W
Pharmaceutical Institute and Physiological Institute, University of Kiel, 24118 Kiel, Germany.
J Med Chem. 1998 Nov 5;41(23):4542-9. doi: 10.1021/jm981032o.
A series of psoralens and structurally related 5,7-disubstituted coumarins was synthesized and investigated for their K+ channel blocking activity as well as for their phototoxicity to Artemia salina and their ability to generate singlet oxygen and to photomodify DNA. After screening the compounds on Ranvier nodes of the toad Xenopus laevis, the affinities of the most promising compounds, which proved to be psoralens bearing alkoxy substituents in the 5-position or alkoxymethyl substituents in the neighboring 4- or 4'-position, to a number of homomeric K+ channels were characterized. All compounds exhibited the highest affinity to Kv1.2. 5,8-Diethoxypsoralen (10d) was found to be an equally potent inhibitor of Kv1.2 and Kv1.3, while lacking the phototoxicity normally inherent in psoralens. The reported compounds represent a novel series of nonpeptide blockers of Shaker-type K+ channels that could be further developed into selective inhibitors of Kv1.2 or Kv1. 3.
合成了一系列补骨脂素及结构相关的5,7 - 二取代香豆素，并对其钾离子通道阻断活性、对卤虫的光毒性、产生单线态氧的能力以及光修饰DNA的能力进行了研究。在用非洲爪蟾的郎飞结筛选这些化合物后，对最有前景的化合物（结果证明是在5 - 位带有烷氧基取代基或在相邻4 - 位或4'- 位带有烷氧甲基取代基的补骨脂素）与多种同聚钾离子通道的亲和力进行了表征。所有化合物对Kv1.2表现出最高亲和力。发现5,8 - 二乙氧基补骨脂素（10d）是Kv1.2和Kv1.3的同等强效抑制剂，同时缺乏补骨脂素通常固有的光毒性。所报道的化合物代表了一类新型的Shaker型钾离子通道非肽类阻滞剂，可进一步开发为Kv1.2或Kv1.3的选择性抑制剂。
