title: Identification and characterization of novel TRPV4 modulators.
abstract: TRPV4, a close relative of the vanilloid receptor TRPV1, is activated by diverse modalities such as endogenous lipid ligands, hypotonicity, protein kinases and, possibly, mechanical inputs. While its multiple roles in vivo are being explored with KO mice and selective agonists, there is a dearth of selective antagonists available to examine TRPV4 function. Herein we detail the use of a focused library of commercial compounds in order to identify RN-1747 and RN-1734, a pair of structurally related small molecules endowed with TRPV4 agonist and antagonist properties, respectively. Their activities against human, rat and mouse TRPV4 were characterized using electrophysiology and intracellular calcium influx. Significantly, antagonist RN-1734 was observed to completely inhibit both ligand- and hypotonicity-activated TRPV4. In addition, RN-1734 was found to be selective for TRPV4 in a TRP selectivity panel including TRPV1, TRPV3 and TRPM8, and could thus be a valuable pharmacological probe for TRPV4 studies.
authors.affiliation: In Vitro Pharmacology Department, Renovis, Inc., South San Francisco, CA 94080, USA. fabien.vincent@evotec.com
authors.forename: Fabien
authors.initials: F
authors.lastname: Vincent
authors.forename: Alejandra
authors.initials: A
authors.lastname: Acevedo
authors.forename: Margaret T
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Michelle
authors.initials: M
authors.lastname: Dourado
authors.forename: Jeff
authors.initials: J
authors.lastname: DeFalco
authors.forename: Amy
authors.initials: A
authors.lastname: Gustafson
authors.forename: Peter
authors.initials: P
authors.lastname: Spiro
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Emerling
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.forename: Matthew A J
authors.initials: MA
authors.lastname: Duncton
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D051381:Rats; D013449:Sulfonamides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000819:agonists* / Q000037:antagonists & inhibitors*; D014981:Xenopus
chemical_list: C544743:RN 1734; C544742:RN 1747; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human