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

Publication ,  Journal Article
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 ...
Published in: Sci Rep
June 1, 2016

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.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 1, 2016

Volume

6

Start / End Page

26894

Location

England

Related Subject Headings

  • Trigeminal Ganglion
  • Thiazoles
  • TRPV Cation Channels
  • TRPA1 Cation Channel
  • Swine
  • Rats
  • Primary Cell Culture
  • Pancreatitis, Acute Necrotizing
  • Pain
  • Nociception
 

Citation

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Kanju, P., Chen, Y., Lee, W., Yeo, M., Lee, S. H., Romac, J., … Liedtke, W. B. (2016). Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep, 6, 26894. https://doi.org/10.1038/srep26894
Kanju, Patrick, Yong Chen, Whasil Lee, Michele Yeo, Suk Hee Lee, Joelle Romac, Rafiq Shahid, et al. “Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.Sci Rep 6 (June 1, 2016): 26894. https://doi.org/10.1038/srep26894.
Kanju P, Chen Y, Lee W, Yeo M, Lee SH, Romac J, et al. Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep. 2016 Jun 1;6:26894.
Kanju, Patrick, et al. “Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.Sci Rep, vol. 6, June 2016, p. 26894. Pubmed, doi:10.1038/srep26894.
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. Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep. 2016 Jun 1;6:26894.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 1, 2016

Volume

6

Start / End Page

26894

Location

England

Related Subject Headings

  • Trigeminal Ganglion
  • Thiazoles
  • TRPV Cation Channels
  • TRPA1 Cation Channel
  • Swine
  • Rats
  • Primary Cell Culture
  • Pancreatitis, Acute Necrotizing
  • Pain
  • Nociception