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

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Date
2016-06-01
Authors
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
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(15 total)
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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.
Type
Journal article
Permalink
https://hdl.handle.net/10161/12075
Published Version (Please cite this version)
10.1038/srep26894
Publication Info
Kanju, P; Chen, Y; Lee, W; Yeo, M; Lee, SH; Romac, J; ... Liedtke, WB (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 https://hdl.handle.net/10161/12075.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Chen

Yong Chen

Associate Professor in Neurology
Dr. Yong Chen is an Associate Professor of Neurology at the Duke University School of Medicine.  He is also affiliated with Duke Anesthesiology-Center for Translational Pain Medicine (CTPM) and Duke-Pathology. The Chen lab mainly studies sensory neurobiology of pain and itch, with a focus on TRP ion channels and neural circuits. The main objective of our lab is to identify molecular and cellular mechanisms underlying chronic pain and chronic-disease associated itch, using a combi

Farshid Guilak

Lazlo Ormandy Professor of Orthopaedic Surgery
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Liddle

Rodger Alan Liddle

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
Liedtke

Wolfgang Bernhard Liedtke

Adjunct Professor in the Department 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.
Mook

Robert Anthony Mook Jr.

Assistant Professor in Medicine

Sidney Arthur Simon

Professor Emeritus of Neurobiology
Dr. Simon's laboratory studies the interaction of chemical stimuli with cultured and intact trigeminal ganglion neurons and taste receptor cells both in culture, in anesthetized and in awake behaving animals. We investigate how chemicals that are either bitter and/or irritating ( e.g., nicotine, capsaicin, colloidal particles) interact with particular types of receptors (e.g. nicotinic acetylcholine receptors or vanilloid receptors) to produce a bitter, irritating or painful sensation. We a
Spasojevic

Ivan Spasojevic

Associate Professor in Medicine
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