REVISTA

Inhibidores duales de moléculas pequeñas de TRPV4 y TRPA1 para atenuar la inflamación y el dolor

Descripción: Nuevo compuesto es capaz de inhibir TRPV1 y TRPV4

TITULO FUENTE ORIGINAL:

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

AUTORES:

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

REVISTA ABREV.:

Sci Rep

AÑO:

2016

REFERENCIA:

6:26894

DOI:

10.1038/srep26894

RESUMEN ORIGINAL:

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... + Leer más

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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Enlace al pdf de acceso libre: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC[...]