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

dc.contributor.author Chen, Y
dc.contributor.author Fan, P
dc.contributor.author Gooden, DM
dc.contributor.author Guilak, Farshid
dc.contributor.author Kanju, Patrick
dc.contributor.author Lee, SH
dc.contributor.author Lee, W
dc.contributor.author Liddle, Rodger Alan
dc.contributor.author Liedtke, Wolfgang Bernhard
dc.contributor.author Mook, RA
dc.contributor.author Romac, J
dc.contributor.author Shahid, Rafiq
dc.contributor.author Simon, SA
dc.contributor.author Spasojević, Ivan
dc.contributor.author Yeo, M
dc.coverage.spatial England
dc.date.accessioned 2016-06-02T18:27:50Z
dc.date.issued 2016-06-01
dc.identifier https://www.ncbi.nlm.nih.gov/pubmed/27247148
dc.identifier srep26894
dc.identifier.uri http://hdl.handle.net/10161/12075
dc.description.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.
dc.language eng
dc.relation.ispartof Sci Rep
dc.relation.isversionof 10.1038/srep26894
dc.title Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
dc.type Journal article
pubs.author-url https://www.ncbi.nlm.nih.gov/pubmed/27247148
pubs.begin-page 26894
pubs.organisational-group Anesthesiology
pubs.organisational-group Basic Science Departments
pubs.organisational-group Biomedical Engineering
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Institute for Brain Sciences
pubs.organisational-group Institutes and Centers
pubs.organisational-group Institutes and Provost's Academic Units
pubs.organisational-group Medicine
pubs.organisational-group Medicine, Gastroenterology
pubs.organisational-group Medicine, Medical Oncology
pubs.organisational-group Neurobiology
pubs.organisational-group Neurology
pubs.organisational-group Neurology, Headache and Pain
pubs.organisational-group Pratt School of Engineering
pubs.organisational-group School of Medicine
pubs.organisational-group University Institutes and Centers
pubs.publication-status Published online
pubs.volume 6
dc.identifier.eissn 2045-2322


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