Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
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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.
Published Version (Please cite this version)10.1038/srep26894
Publication InfoChen, Y; Fan, P; Gooden, DM; Guilak, Farshid; Kanju, Patrick; Lee, SH; ... Yeo, M (2016). Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep, 6. pp. 26894. 10.1038/srep26894. Retrieved from http://hdl.handle.net/10161/12075.
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Lazlo Ormandy Professor of Orthopaedic Surgery
Professor of Medicine
Our laboratory has two major research interests:Enteroendocrine Cell Biology Enteroendocrine cells (EECs) are sensory cells of the gut that send signals throughout the body. They have the ability to sense food and nutrients in the lumen of the intestine and secrete hormones into the blood. Our laboratory has had a longstanding interest in two types of EECs that regulate satiety and signal the brain to stop eating. Chole
Professor of Neurology
Research Interests in the Liedtke-Lab: Pain/ nociception Sensory transduction and -transmission TRP ion channels Water and salt equilibrium regulated by the central nervous system Visit the lab's website, download papers and read Dr. Liedtke's CV here.
Associate Professor in Medicine
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