title: 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.
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kanju
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.
authors.forename: Whasil
authors.initials: W
authors.lastname: Lee
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Yeo
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.
authors.forename: Suk Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.
authors.forename: Joelle
authors.initials: J
authors.lastname: Romac
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.
authors.forename: Rafiq
authors.initials: R
authors.lastname: Shahid
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.affiliation: Dept of Chemistry, Duke University, Durham NC USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Gooden
authors.affiliation: Dept of Neurobiology, Duke University, Durham NC USA.
authors.forename: Sidney A
authors.initials: SA
authors.lastname: Simon
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.|Dept of Chemistry, Duke University, Durham NC USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mook
authors.affiliation: Dept of Medicine, Duke University, Durham NC USA.
authors.forename: Rodger A
authors.initials: RA
authors.lastname: Liddle
authors.affiliation: Dept of Orthopedic Surgery, Washington University in St Louis and Shriners Hospitals for Children, St Louis MO USA.
authors.forename: Farshid
authors.initials: F
authors.lastname: Guilak
authors.affiliation: Dept of Neurology, Duke University, Durham NC USA.|Dept of Neurobiology, Duke University, Durham NC USA.|Dept of Anesthesiology, Duke University, Durham NC USA.|Neurology Clinics for Headache, Head-Pain and Trigeminal Sensory Disorders, Duke University, Durham NC USA.
authors.forename: Wolfgang B
authors.initials: WB
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002108:Ceruletide; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D061251:Primary Cell Culture; D051381:Rats; D013552:Swine; D000074025:TRPA1 Cation Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; D013844:Thiazoles; D002108:Ceruletide