Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
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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https://hdl.handle.net/10161/12075Published Version (Please cite this version)
10.1038/srep26894Publication 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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Show full item recordScholars@Duke
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.
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
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.
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
Ivan Spasojevic
Associate Professor in Medicine
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