title: A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid.
abstract: The vanilloid receptor transient receptor potential type V1 (TRPV1) integrates responses to multiple stimuli, such as capsaicin, acid, heat, and endovanilloids and plays an important role in the transmission of inflammatory pain. Here, we report the identification and in vitro characterization of A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel, potent, and selective TRPV1 antagonist. A-425619 was found to potently block capsaicin-evoked increases in intracellular calcium concentrations in HEK293 cells expressing recombinant human TRPV1 receptors (IC50 = 5 nM). A-425619 showed similar potency (IC50 = 3-4 nM) to block TRPV1 receptor activation by anandamide and N-arachidonoyl-dopamine. Electrophysiological experiments showed that A-425619 also potently blocked the activation of native TRPV1 channels in rat dorsal root ganglion neurons (IC50 = 9 nM). When compared with other known TRPV1 antagonists, A-425619 exhibited superior potency in blocking both naive and phorbol ester-sensitized TRPV1 receptors. Like capsazepine, A-425619 demonstrated competitive antagonism (pA2 = 2.5 nM) of capsaicin-evoked calcium flux. Moreover, A-425619 was 25- to 50-fold more potent than capsazepine in blocking TRPV1 activation. A-425619 showed no significant interaction with a wide range of receptors, enzymes, and ion channels, indicating a high degree of selectivity for TRPV1 receptors. These data show that A-425619 is a structurally novel, potent, and selective TRPV1 antagonist.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. rachid.elkouhen@abbott.com
authors.forename: Rachid
authors.initials: R
authors.lastname: El Kouhen
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: Torben R
authors.initials: TR
authors.lastname: Neelands
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
mesh_terms: D000143:Acids; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004594:Electrophysiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D006358:Hot Temperature; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000187:drug effects; D050916:TRPV Cation Channels; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C503120:1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; D000143:Acids; D007473:Ion Channels; D007546:Isoquinolines; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014508:Urea; D002118:Calcium