PT  - JOURNAL ARTICLE
AU  - Rachid El Kouhen
AU  - Carol S. Surowy
AU  - Bruce R. Bianchi
AU  - Torben R. Neelands
AU  - Heath A. McDonald
AU  - Wende Niforatos
AU  - Arthur Gomtsyan
AU  - Chih-Hung Lee
AU  - Prisca Honore
AU  - James P. Sullivan
AU  - Michael F. Jarvis
AU  - Connie R. Faltynek
TI  - 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
AID  - 10.1124/jpet.105.084103
DP  - 2005 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 400--409
VI  - 314
IP  - 1
4099  - http://jpet.aspetjournals.org/content/314/1/400.short
4100  - http://jpet.aspetjournals.org/content/314/1/400.full
SO  - J Pharmacol Exp Ther2005 Jul 01; 314
AB  - 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 estersensitized TRPV1 receptors. Like capsazepine, A-425619 demonstrated competitive antagonism (pA2 = 2.5 nM) of capsaicinevoked 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. The American Society for Pharmacology and Experimental Therapeutics