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

  • Sci Rep. 2016 Jun 1;6:26894. doi: 10.1038/srep26894.
Patrick Kanju  1 ,  Yong Chen  1 ,  Whasil Lee  1 ,  Michele Yeo  1 ,  Suk Hee Lee  1 ,  Joelle Romac  2 ,  Rafiq Shahid  2 ,  Ping Fan  2 ,  David M Gooden  3 ,  Sidney A Simon  4 ,  Ivan Spasojevic  2 ,  Robert A Mook  2  3 ,  Rodger A Liddle  2 ,  Farshid Guilak  5 ,  Wolfgang B Liedtke  1  4  6  7
Affiliations
  • 1. Dept of Neurology, Duke University, Durham NC USA.
  • 2. Dept of Medicine, Duke University, Durham NC USA.
  • 3. Dept of Chemistry, Duke University, Durham NC USA.
  • 4. Dept of Neurobiology, Duke University, Durham NC USA.
  • 5. Dept of Orthopedic Surgery, Washington University in St Louis and Shriners Hospitals for Children, St Louis MO USA.
  • 6. Dept of Anesthesiology, Duke University, Durham NC USA.
  • 7. Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University, Durham NC USA.
PMID: 27247148 DOI: 10.1038/srep26894
Abstract

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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