Design, synthesis, and BK channel-opening activity of hexahydrodibenzazepinone derivatives
Design, synthesis, and BK channel-opening activity of hexahydrodibenzazepinone derivatives
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DOI：
10.1016/j.bmc.2006.07.042
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发表时间：
2006-12-01
影响因子：
3.5
通讯作者：
Ohwada, Tomohiko
中科院分区：
文献类型：
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作者：
Tashima, Toshihiko;Toriumi, Yoshimi;Ohwada, Tomohiko
为了探索大电导钙激活钾通道（BK通道）开放剂的新骨架，我们基于以下两个概念进行了分子设计和合成：（1）在脱氢枞酸（BK通道开放剂）骨架上引入杂原子，可以更容易地引入取代基。(2)由于BK通道的四重对称结构，其中两个药效团通过系链连接的二聚体化合物预期具有更大的与通道结合的可能性，导致增加的通道开放活性。在此，我们探索六氢二苯并氮杂卓酮结构作为BK通道开放剂的新支架的有用性。合成的单体化合物的六氢二苯并氮杂卓酮衍生物，它可以来自脱氢松香酸，进行电生理膜片钳研究，然后通过马格努斯收缩-舒张试验，使用兔膀胱平滑肌条，以评估整体活动。通过二乙炔基苯系链连接单体六氢二苯并氮杂卓酮衍生物，设计了二聚化合物，并通过电生理方法评价了其通道开放活性。最后，我们得出结论，BK通道开放活性的关键结构是六氢二苯并氮杂卓一个单体被内酰胺酰胺上的苯基炔基取代基取代。(c)2006爱思唯尔有限公司版权所有。
In order to explore new scaffolds for large-conductance Ca2+ -activated K+ channel (BK channel) openers, we carried out molecular design and synthesis on the basis of the following two concepts: (1) introduction of a heteroatom into the dehydroabietic acid (BK channel opener) skeleton would allow easier introduction of substituents. (2) Because of the fourfold symmetrical structure of BK channels, dimeric compounds in which two pharmacophores are linked through a tether are expected to have a greater binding probability to the channels, resulting in increased channel-opening activity. Herein, we explore the usefulness of the hexahydrodibenzazepinone structure as a new scaffold for BK channel openers. The synthesized monomer compounds of hexahydrodibenzazepinone derivatives, which can be derived from dehydroabietic acid, were subjected to electrophysiological patch-clamp studies, followed by Magnus contraction-relaxation assay using rabbit urinary bladder smooth muscle strips to assess overall activities. Dimeric compounds were designed by linking the monomeric hexahydrodibenzazepinone derivatives through a diacetylenebenzene tether, and their channel-opening activities were evaluated by electrophysiological methods. Finally, we concluded that the critical structure for BK channel-opening activity is the hexahydrodibenzazepin one monomer substituted with a phenyl-bearing alkynyl substituent on the lactam amide. (c) 2006 Elsevier Ltd. All rights reserved.