Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain.
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.
Duke Scholars
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Related Subject Headings
- Trigeminal Ganglion
- Thiazoles
- TRPV Cation Channels
- TRPA1 Cation Channel
- Swine
- Rats
- Primary Cell Culture
- Pancreatitis, Acute Necrotizing
- Pain
- Nociception
Citation
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- Trigeminal Ganglion
- Thiazoles
- TRPV Cation Channels
- TRPA1 Cation Channel
- Swine
- Rats
- Primary Cell Culture
- Pancreatitis, Acute Necrotizing
- Pain
- Nociception