4.7 Article

Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain

Journal

SCIENTIFIC REPORTS
Volume 6, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/srep26894

Keywords

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Funding

  1. NIH/NCI Comprehensive Cancer Center [2P30-CA014236-41]
  2. National Institutes of Health [DE018549, AR48182, AR48182-S1, AR48852, AG15768, AR50245, AG46927, DK064213, DK091946, DK098796, F33DE024668, K12DE022793, K12CA100639]
  3. US Department of Defense [W81XWH-13-1-0299]
  4. US Department of Veterans Affairs
  5. NSF [1445792]
  6. Arthritis Foundation
  7. Harrington Discovery Institute (Cleveland OH)
  8. Div Of Civil, Mechanical, & Manufact Inn
  9. Directorate For Engineering [1445792] Funding Source: National Science Foundation

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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.

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