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


Autoria(s): 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
Cobertura

England

Data(s)

2016

Resumo

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.

Formato

26894 - ?

Identificador

http://www.ncbi.nlm.nih.gov/pubmed/27247148

srep26894

Sci Rep, 2016, 6 pp. 26894 - ?

http://hdl.handle.net/10161/12075

2045-2322

Idioma(s)

eng

Relação

Sci Rep

10.1038/srep26894

Tipo

Journal Article