Referenced in: none

Automatically associated channels: SK2 , TRP , TRPA , TRPA1 , TRPV , TRPV4

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

Authors: Patrick Kanju, Yong Chen, Whasil Lee, Michele Yeo, Suk Hee Lee, Joelle Romac, Rafiq Shahid, Ping Fan, David M Gooden, Sidney A Simon, Ivan Spasojević, Robert A Mook, Rodger A Liddle, Farshid Guilak, Wolfgang B Liedtke

Journal, date & volume: Sci Rep, 2016 , 6, 26894

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/27247148

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.