Triarylmethanes, a new class of cx50 inhibitors.
Triarylmethanes, a new class of cx50 inhibitors.
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DOI：
10.3389/fphar.2012.00106
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发表时间：
2012
影响因子：
5.6
通讯作者：
Srinivas M
中科院分区：
文献类型：
--
作者：
Bodendiek SB;Rubinos C;Trelles MP;Coleman N;Jenkins DP;Wulff H;Srinivas M
缺乏特异性的药理学药物一直是描述由连接蛋白形成的间隙连接（GJ）通道在生理学和病理生理学中的作用的主要障碍。在这里，我们使用了选择性优化的副作用（SOSA）的方法，这导致了其他离子通道的高亲和力抑制剂的设计，以确定由Cx 50，连接蛋白亚型，主要是在透镜中表达的通道形成的特异性抑制剂。我们最初筛选了一个共同的离子通道调节药效团的库，其对Cx 50 GJ通道的抑制作用，并确定了四个新的化合物类别。三芳基甲烷（TRAM）克霉唑是最有效的Cx 50抑制剂，因此，我们使用它作为模板，探索结构活性关系（SAR）的TRAM的Cx 50抑制。我们描述了T122（N-[（2-甲氧基苯基）二苯甲基]-1，3-噻唑-2-胺）和T136（N-[（2-碘苯基）二苯甲基]-1，3-噻唑-2-胺）的设计，其抑制Cx 50的IC 50为1.2和2.4 μM。这两种化合物表现出至少10倍的选择性超过其他连接蛋白以及主要的神经元和心脏电压门控K+和Na+通道。SAR研究还表明，连接蛋白抑制所需的TRAM药效团与阻断钙激活的KCa3.1通道所需的药效团显著不同。T122和T136均选择性抑制透镜上皮细胞Cx 50 GJ通道，提示T122和T136可用于进一步探讨Cx 50在透镜中的作用。此外，我们的研究结果表明，类似的方法可用于寻找其他连接蛋白亚型的特异性抑制剂。
The paucity of specific pharmacological agents has been a major impediment for delineating the roles of gap junction (GJ) channels formed by connexin proteins in physiology and pathophysiology. Here, we used the selective optimization of side activities (SOSA) approach, which has led to the design of high affinity inhibitors of other ion channels, to identify a specific inhibitor for channels formed by Cx50, a connexin subtype that is primarily expressed in the lens. We initially screened a library of common ion channel modulating pharmacophores for their inhibitory effects on Cx50 GJ channels, and identified four new classes of compounds. The triarlymethane (TRAM) clotrimazole was the most potent Cx50 inhibitor and we therefore used it as a template to explore the structure activity relationship (SAR) of the TRAMs for Cx50 inhibition. We describe the design of T122 (N-[(2-methoxyphenyl)diphenylmethyl]-1,3-thiazol-2-amine) and T136 (N-[(2-iodophenyl)diphenylmethyl]-1,3-thiazol-2-amine), which inhibit Cx50 with IC50s of 1.2 and 2.4 μM. Both compounds exhibit at least 10-fold selectivity over other connexins as well as major neuronal and cardiac voltage-gated K+ and Na+ channels. The SAR studies also indicated that the TRAM pharmacophore required for connexin inhibition is significantly different from the pharmacophore required for blocking the calcium-activated KCa3.1 channel. Both T122 and T136 selectively inhibited Cx50 GJ channels in lens epithelial cells, suggesting that they could be used to further explore the role of Cx50 in the lens. In addition, our results indicate that a similar approach may be used to find specific inhibitors of other connexin subtypes.
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DOI：
10.1073/pnas.0402044101
发表时间：
2004-08-17
影响因子：
11.1
作者：
Cruikshank, SJ;Hopperstadt, M;Srinivas, M
通讯作者：
Srinivas, M
影响因子：
3.6
作者：
Sankaranarayanan, Ananthakrishnan;Raman, Girija;Busch, Christoph;Schultz, Tim;Zimin, Pavel I.;Hoyer, Joachim;Koehler, Ralf;Wulff, Heike
通讯作者：
Wulff, Heike
影响因子：
33.6
作者：
Mathias RT;White TW;Gong X
通讯作者：
Gong X
DOI：
10.1073/pnas.191206198
发表时间：
2001-09-11
影响因子：
11.1
作者：
Srinivas, M;Hopperstad, MG;Spray, DC
通讯作者：
Spray, DC
影响因子：
3.5
作者：
Locovei, Silviu;Scemes, Eliana;Dahl, Gerhard
通讯作者：
Dahl, Gerhard