期刊
SCIENTIFIC REPORTS
卷 6, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep26894
关键词
-
资金
- NIH/NCI Comprehensive Cancer Center [2P30-CA014236-41]
- National Institutes of Health [DE018549, AR48182, AR48182-S1, AR48852, AG15768, AR50245, AG46927, DK064213, DK091946, DK098796, F33DE024668, K12DE022793, K12CA100639]
- US Department of Defense [W81XWH-13-1-0299]
- US Department of Veterans Affairs
- NSF [1445792]
- Arthritis Foundation
- Harrington Discovery Institute (Cleveland OH)
- Div Of Civil, Mechanical, & Manufact Inn
- Directorate For Engineering [1445792] Funding Source: National Science Foundation
TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and widespread 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据