Identification and characterization of novel TRPV4 modulators.
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.
Vincent
Fabien
F
In Vitro Pharmacology Department, Renovis, Inc., South San Francisco, CA 94080, USA. fabien.vincent@evotec.com
Acevedo
Alejandra
A
Nguyen
Margaret T
MT
Dourado
Michelle
M
DeFalco
Jeff
J
Gustafson
Amy
A
Spiro
Peter
P
Emerling
Daniel E
DE
Kelly
Michael G
MG
Duncton
Matthew A J
MA
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
C544743:RN 1734; C544742:RN 1747; D013449:Sulfonamides; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human