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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.
J Pharmacol Exp Ther. 2005 Jul; 314(1):400-9.JP

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+Show Affiliations

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. rachid.elkouhen@abbott.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15837819

Citation

El Kouhen, Rachid, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 314, no. 1, 2005, pp. 400-9.
El Kouhen R, Surowy CS, Bianchi BR, et al. 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. J Pharmacol Exp Ther. 2005;314(1):400-9.
El Kouhen, R., Surowy, C. S., Bianchi, B. R., Neelands, T. R., McDonald, H. A., Niforatos, W., Gomtsyan, A., Lee, C. H., Honore, P., Sullivan, J. P., Jarvis, M. F., & Faltynek, C. R. (2005). 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. The Journal of Pharmacology and Experimental Therapeutics, 314(1), 400-9.
El Kouhen R, et al. 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. J Pharmacol Exp Ther. 2005;314(1):400-9. PubMed PMID: 15837819.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - El Kouhen,Rachid, AU - Surowy,Carol S, AU - Bianchi,Bruce R, AU - Neelands,Torben R, AU - McDonald,Heath A, AU - Niforatos,Wende, AU - Gomtsyan,Arthur, AU - Lee,Chih-Hung, AU - Honore,Prisca, AU - Sullivan,James P, AU - Jarvis,Michael F, AU - Faltynek,Connie R, Y1 - 2005/04/18/ PY - 2005/4/20/pubmed PY - 2005/8/27/medline PY - 2005/4/20/entrez SP - 400 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 314 IS - 1 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15837819/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_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15837819 DB - PRIME DP - Unbound Medicine ER -