Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
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TRPV4和TRPA1的小分子双抑制剂，用于炎症和疼痛的衰减。
DOI：
10.1038/srep26894
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发表时间：
2016-06-01
影响因子：
4.6
通讯作者：
Liedtke WB
中科院分区：
文献类型：
--
作者：
Kanju P;Chen Y;Lee W;Yeo M;Lee SH;Romac J;Shahid R;Fan P;Gooden DM;Simon SA;Spasojevic I;Mook RA;Liddle RA;Guilak F;Liedtke WB
TRPV4 离子通道代表具有多效性功能和广泛表达的渗透-机械-TRP 通道。 TRPV4 在该谱系中的关键功能之一是它参与疼痛和炎症。然而，TRPV4 的小分子抑制剂很少。在这里，我们基于已知的 TRPV4 选择性工具化合物 GSK205 的修饰开发了 TRPV4 抑制分子。我们不仅增加了 TRPV4 的抑制效力，而且令人惊讶的是还产生了两种有效共同抑制 TRPA1 的化合物，TRPA1 已知用作有害和刺激性信号传导的化学传感器。我们证明了这些化合物在具有已知 TRPV4 表达的原代细胞（关节软骨细胞和星形胶质细胞）中对 TRPV4 的抑制作用。重要的是，我们的新型化合物可以减轻三叉神经刺激性疼痛模型中的疼痛行为，该模型已知依赖于 TRPV4 和 TRPA1。此外，我们的新型双通道阻滞剂抑制了急性胰腺炎模型中的炎症和疼痛相关行为——已知该模型也依赖于 TRPV4 和 TRPA1。我们的结果证明了我们的药物原型化合物固有的新概念，该药物靶向两个功能相关的 TRP 通道，因此可用于对抗涉及多个 TRP 通道的体内疼痛和炎症亚型。这种方法可以为治疗其他相关健康状况提供一种新的范例。
TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis – known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions.