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

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

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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.

Original languageEnglish
Article number26894
JournalScientific reports
Volume6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Dive into the research topics of 'Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain'. Together they form a unique fingerprint.

Cite this