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James P Sullivan - One of the best experts on this subject based on the ideXlab platform.
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a 425619 1 isoquinolin 5 yl 3 4 trifluoromethyl benzyl urea a novel transient receptor potential type v1 receptor antagonist relieves pathophysiological pain associated with inflammation and tissue injury in rats
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Prisca Honore, Carol T Wismer, Joseph P Mikusa, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Kennan C Marsh, James P Sullivan, Connie R FaltynekAbstract:The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N -arachidonoyl-Dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
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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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Rachid El Kouhen, Prisca Honore, Arthur Gomtsyan, Heath A Mcdonald, Torben R Neelands, Carol S Surowy, Bruce R Bianchi, Wende Niforatos, Chihhung Lee, James P SullivanAbstract: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 (p A 2 = 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.
Rachid El Kouhen - One of the best experts on this subject based on the ideXlab platform.
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a 425619 1 isoquinolin 5 yl 3 4 trifluoromethyl benzyl urea a novel transient receptor potential type v1 receptor antagonist relieves pathophysiological pain associated with inflammation and tissue injury in rats
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Prisca Honore, Carol T Wismer, Joseph P Mikusa, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Kennan C Marsh, James P Sullivan, Connie R FaltynekAbstract:The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N -arachidonoyl-Dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
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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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Rachid El Kouhen, Prisca Honore, Arthur Gomtsyan, Heath A Mcdonald, Torben R Neelands, Carol S Surowy, Bruce R Bianchi, Wende Niforatos, Chihhung Lee, James P SullivanAbstract: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 (p A 2 = 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.
Prisca Honore - One of the best experts on this subject based on the ideXlab platform.
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a 425619 1 isoquinolin 5 yl 3 4 trifluoromethyl benzyl urea a novel transient receptor potential type v1 receptor antagonist relieves pathophysiological pain associated with inflammation and tissue injury in rats
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Prisca Honore, Carol T Wismer, Joseph P Mikusa, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Kennan C Marsh, James P Sullivan, Connie R FaltynekAbstract:The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N -arachidonoyl-Dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
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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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Rachid El Kouhen, Prisca Honore, Arthur Gomtsyan, Heath A Mcdonald, Torben R Neelands, Carol S Surowy, Bruce R Bianchi, Wende Niforatos, Chihhung Lee, James P SullivanAbstract: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 (p A 2 = 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.
Arthur Gomtsyan - One of the best experts on this subject based on the ideXlab platform.
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a 425619 1 isoquinolin 5 yl 3 4 trifluoromethyl benzyl urea a novel transient receptor potential type v1 receptor antagonist relieves pathophysiological pain associated with inflammation and tissue injury in rats
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Prisca Honore, Carol T Wismer, Joseph P Mikusa, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Kennan C Marsh, James P Sullivan, Connie R FaltynekAbstract:The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N -arachidonoyl-Dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
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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
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Rachid El Kouhen, Prisca Honore, Arthur Gomtsyan, Heath A Mcdonald, Torben R Neelands, Carol S Surowy, Bruce R Bianchi, Wende Niforatos, Chihhung Lee, James P SullivanAbstract: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 (p A 2 = 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.
Connie R Faltynek - One of the best experts on this subject based on the ideXlab platform.
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a 425619 1 isoquinolin 5 yl 3 4 trifluoromethyl benzyl urea a novel transient receptor potential type v1 receptor antagonist relieves pathophysiological pain associated with inflammation and tissue injury in rats
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Prisca Honore, Carol T Wismer, Joseph P Mikusa, Chengmin Zhong, Donna M Gauvin, Arthur Gomtsyan, Rachid El Kouhen, Kennan C Marsh, James P Sullivan, Connie R FaltynekAbstract:The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N -arachidonoyl-Dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 μmol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 μmol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 μmol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.
