Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels.
Design and synthesis of hydroxy-alkynoic acids and their methyl esters as novel activators of BK channels.
复制标题
羟基炔酸及其甲酯作为 BK 通道新型激活剂的设计和合成。
DOI：
10.1016/j.bmcl.2008.03.080
复制
发表时间：
2008
影响因子：
2.7
通讯作者：
Miller,Duane
中科院分区：
文献类型：
--
作者：
Patil,Shivaputra;Bukiya,AnnaN;Li,Wei;Dopico,AlejandroM;Miller,Duane
激活位于平滑肌中的大电导、电压和钙门控钾（BK）通道的生理和药理学药物是有效的血管扩张剂。因此，平滑肌BK通道激活剂可能是治疗与血管收缩和/或扩张受损相关的心血管疾病（如脑血管痉挛和收缩）的潜在治疗工具。我们之前的研究表明，石胆酸（LC）和其他胆烷衍生物激活平滑肌BK通道，从而引起不依赖内皮的脑动脉扩张。然而，这些胆烷衍生物的临床使用可能受到这些类固醇作用的限制，如细胞内钙升高和诱导细胞凋亡。以LC为模板，我们设计并合成了一系列的羟基炔烃酸和相应的甲酯，作为推定的非甾体BK通道激活剂。事实上，新合成的化合物有效且可逆地激活大鼠脑血管肌细胞BK通道，其浓度与LC相似。在所有测试的新化合物中，C-10羟基炔烃酸甲酯似乎是血管肌细胞BK通道最有效的激活剂。
Physiological and pharmacological agents that activate large conductance, voltage-, and calcium-gated potassium (BK) channels located in the smooth muscle are effective vasodilators. Thus, activators of smooth muscle BK channels may be potential therapeutic tools to treat cardiovascular disease associated with vasoconstriction and/or impaired dilation, such as cerebrovascular spasm and constriction. We previously showed that lithocholic acid (LC) and other cholane derivatives activated smooth muscle BK channels and, thus, caused endothelium-independent cerebral artery dilation. However, clinical use of these cholane derivatives could be limited by the actions of these steroids, such as elevation of intracellular calcium and induction of apoptosis. Using LC as template, we designed and synthesized a series of hydroxy-alkynoic acids and corresponding methyl esters, as putative, non-steroid BK channel activators. Indeed, the newly synthesized compounds effectively and reversibly activated rat cerebrovascular myocyte BK channel at concentrations similar to those found effective with LC. Among all the novel compounds tested, C-10 hydroxy-alkynoic acid methyl ester appears to be the most effective activator of vascular myocyte BK channels.
DOI：
10.1046/j.1365-201x.1998.00462.x
发表时间：
1998-12
期刊：
Acta physiologica Scandinavica
影响因子：
--
作者：
J. Jaggar;G. Wellman;T. Heppner;V. Porter;G. Pérez;M. Gollasch;T. Kleppisch;M. Rubart;A. Stevenson;W. J. Lederer;H. Knot;A. Bonev;M. Nelson
通讯作者：
J. Jaggar;G. Wellman;T. Heppner;V. Porter;G. Pérez;M. Gollasch;T. Kleppisch;M. Rubart;A. Stevenson;W. J. Lederer;H. Knot;A. Bonev;M. Nelson
影响因子：
3.6
作者：
A. Dopico;JoséR. Lemos;S. Treistman
通讯作者：
A. Dopico;JoséR. Lemos;S. Treistman
影响因子：
56.9
作者：
BRAYDEN, JE;NELSON, MT
通讯作者：
NELSON, MT