Dantrolene analogues revisited:: General synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle
Dantrolene analogues revisited:: General synthesis and specific functions capable of discriminating two kinds of Ca2+ release from sarcoplasmic reticulum of mouse skeletal muscle
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DOI：
10.1016/s0968-0896(02)00600-4
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发表时间：
2003-03-06
影响因子：
3.5
通讯作者：
Suzuki, M
中科院分区：
文献类型：
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作者：
Hosoya, T;Aoyama, H;Suzuki, M
通过钯催化的交叉偶联反应（如施蒂勒反应或铃木反应作为关键步骤），已经开发出在其苯环上具有各种取代基的丹曲林类似物的一般合成方法。通过基于以下两种从小鼠骨骼肌纤维肌浆网（SR）释放Ca²⁺的模式评估了合成类似物的效果：（1）测量完整骨骼肌生理Ca²⁺释放（PCR）引起的抽搐收缩；（2）在经皂苷处理的去皮肌纤维中Ca²⁺诱导的Ca²⁺释放（CICR）速率。尽管先导化合物丹曲林对抽搐收缩和CICR都有抑制作用，但一些结构修饰的类似物表现出其中一种或另一种作用。甲氧基同系物GIF - 0185在不影响CICR的情况下强烈抑制抽搐收缩，而邻硝基区域异构体GIF - 0166和邻、邻二硝基取代类似物GIF - 0248分别专门对CICR有双重增强作用。（C）2002爱思唯尔科学有限公司。保留所有权利。
The general synthesis of dantrolene analogues with various substituents on its phenyl ring has been developed via palladium-catalyzed cross-coupling reactions, the Stille or Suzuki reaction, as the key step. The effects of synthesized analogues have been evaluated by two kinds of Ca2+ release modes from sarcoplasmic reticulum (SR) of mouse skeletal muscle fibers based on: (1) the measurement of twitch contraction caused by the physiological Ca2+ release (PCR) of intact skeletal muscle and (2) the rate of Ca2+-induced Ca2+ release (CICR) in saponin-treated skinned muscle fibers. Although dantrolene, a lead compound, inhibits both twitch contraction and CICR, some structurally modified analogues exhibit one or the other of these effects. The methoxy congener, GIF-0185, potently inhibits the twitch contraction without affecting the CICR, while GIF-0166 and GIF-0248, the ortho-nitro regioisomer and ortho, ortho-dinitro substituted analogues, respectively, doubly potentiate the CICR exclusively. (C) 2002 Elsevier Science Ltd. All rights reserved.