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Shiazah Malik - One of the best experts on this subject based on the ideXlab platform.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective vanilloid receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
Kenneth J Valenzano - One of the best experts on this subject based on the ideXlab platform.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective vanilloid receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
James T Limberis - One of the best experts on this subject based on the ideXlab platform.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective vanilloid receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
Laykea Tafesse - One of the best experts on this subject based on the ideXlab platform.
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An efficient parallel synthesis of Capsazepine and Capsazepine analogs.
Combinatorial chemistry & high throughput screening, 2004Co-Authors: Laykea Tafesse, Donald J KyleAbstract:Capsazepine (CPZ, 1) is a well-known vanilloid receptor (VR1) antagonist that has been cited widely used in the literature. However the current synthetic methods used for the total synthesis of CPZ are lengthy, involve multiple purification steps, and produce low yields. Here we describe a new and highly efficient synthesis of benzazepine 3, a synthetic precursor of CPZ, in only two steps and 59% overall yield from a commercially available tetralone 2 via a Schmidt reaction as a key step. Moreover, we apply parallel synthesis techniques to prepare CPZ and CPZ analogs. Our approach enables the possibility of preparing larger, and more diverse libraries of CPZ analogs.
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n 4 tertiarybutylphenyl 4 3 chloropyridin 2 yl tetrahydropyrazine 1 2h carbox amide bctc a novel orally effective vanilloid receptor 1 antagonist with analgesic properties i in vitro characterization and pharmacokinetic properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Gang Wu, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, James T Limberis, Shiazah MalikAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N -(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2 H )-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC 50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC 50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of ∼1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
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N-(4-Tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine -1(2H)-carbox-amide (BCTC), a Novel, Orally Effective Vanilloid Receptor 1 Antagonist with Analgesic Properties: I. In Vitro Characterization and Pharmacokinetic Properties
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Kenneth J Valenzano, Elfrida R Grant, Mohamed Hachicha, Lori Schmid, Laykea Tafesse, Yakov Rotshteyn, Joseph Francis, Qun Sun, James T LimberisAbstract:Vanilloids such as capsaicin have algesic properties and seem to mediate their effects via activation of the vanilloid receptor 1 (VR1), a ligand-gated ion channel highly expressed on primary nociceptors. Although blockade of capsaicin-induced VR1 activation has been demonstrated in vitro and in vivo with the antagonist Capsazepine, efficacy in rat models of chronic pain has not been observed with this compound. Here, we describe the in vitro pharmacology of a highly potent VR1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carbox-amide (BCTC). Similar to Capsazepine, this compound inhibits capsaicin-induced activation of rat VR1 with an IC50 value of 35 nM. Interestingly however, BCTC also potently inhibits acid-induced activation of rat VR1 (IC50 value of 6.0 nM), whereas Capsazepine is inactive. Similarly, in the rat skin-nerve preparation both BCTC and Capsazepine block capsaicin-induced activation, whereas the response to acidification is inhibited by BCTC, but not by Capsazepine. Specificity for VR1 was demonstrated against 63 other receptor, enzyme, transporter, and ion channel targets. BCTC was orally bioavailable in the rat, demonstrating a plasma half-life of approximately 1 h and significant penetration into the central nervous system. Thus, BCTC is a high potency, selective VR1 antagonist that, unlike Capsazepine, has potent blocking effects on low pH-induced activation of rat VR1. These properties make it a more suitable candidate than Capsazepine for testing the role played by VR1 in rat models of human disease.
Lena Uller - One of the best experts on this subject based on the ideXlab platform.
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capacity of capsazepinoids to relax human small airways and inhibit tlr3 induced tslp and ifnβ production in diseased bronchial epithelial cells
International Immunopharmacology, 2012Co-Authors: Irma Mahmutovicpersson, Martin Johansson, Angelica Brandelius, Jenny Calven, Leif Bjermer, Yulyana Yudina, Lena UllerAbstract:Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease-inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFNβ is deficient. It is of therapeutic interest that Capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other Capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFNβ effects of Capsazepine and novel Capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) >30 times, more potent than Capsazepine as relaxants of LTD(4)-contracted small airways. TLR3-induced TSLP, TNFα, CXCL8, and IFNβ mRNA and protein levels were dose-dependently and non-selectively inhibited by Capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFNβ but none are more potent than Capsazepine. Only Capsazepine consistently inhibited TNFα and CXCL8 production and attenuated TLR3-induced epithelial NF-κB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNβ, but all compounds, except Capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in Capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFNβ and that these are distinct from mechanisms involved in relaxation of small airways by these compounds. (Less)
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Capacity of capsazepinoids to relax human small airways and inhibit TLR3-induced TSLP and IFNβ production in diseased bronchial epithelial cells.
International Immunopharmacology, 2012Co-Authors: Irma Mahmutovic-persson, Martin Johansson, Angelica Brandelius, Jenny Calven, Leif Bjermer, Yulyana Yudina, Lena UllerAbstract:Thymic stromal lymphopoietin (TSLP), an immunomodulating potentially disease-inducing cytokine, is overproduced in TLR3-stimulated bronchial epithelial cells from asthmatic donors whereas production of antiviral IFNβ is deficient. It is of therapeutic interest that Capsazepine inhibits epithelial TSLP and relaxes human small airways with similar potencies. However, it is not known if other Capsazepine-like compounds share such dual actions. This study explores epithelial anti-TSLP and anti-IFNβ effects of Capsazepine and novel Capsazepine-like bronchorelaxants. We used primary bronchial epithelial cells from asthmatic and chronic obstructive pulmonary disease (COPD) donors, and human small airways dissected from surgically removed lungs. Seven novel capsazepinoids were about 10 times, and one compound (RES187) >30 times, more potent than Capsazepine as relaxants of LTD(4)-contracted small airways. TLR3-induced TSLP, TNFα, CXCL8, and IFNβ mRNA and protein levels were dose-dependently and non-selectively inhibited by Capsazepine, equally in cells from asthmatic and COPD donors. The novel compounds, except RES187, reduced TSLP and IFNβ but none are more potent than Capsazepine. Only Capsazepine consistently inhibited TNFα and CXCL8 production and attenuated TLR3-induced epithelial NF-κB signalling. Hence, the present compounds did not separate between inhibition of TLR3-induced epithelial TSLP and IFNβ, but all compounds, except Capsazepine, did separate between the bronchorelaxant and the epithelial immune effects. We conclude that similar mechanisms may be involved in Capsazepine-like inhibition of TLR3-induced epithelial TSLP and IFNβ and that these are distinct from mechanisms involved in relaxation of small airways by these compounds.
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dsRNA-induced expression of thymic stromal lymphopoietin (TSLP) in asthmatic epithelial cells is inhibited by a small airway relaxant.
Pulmonary Pharmacology & Therapeutics, 2010Co-Authors: Angelica Brandelius, Jenny Calven, Leif Bjermer, Yulyana Yudina, Carl G. A. Persson, Morgan Andersson, Lena UllerAbstract:RATIONALE: Thymic Stromal Lymphopoietin (TSLP) is considered a hub cytokine that activates dendritic cells and T-cells producing asthma-like Th(2)-inflammation. Viral stimuli, a major cause of asthma exacerbations, have been shown to induce overexpression of TSLP in asthmatic epithelium. Capsazepine has multiple effects and is of interest because it relaxes human small airways. Here we have explored effects of Capsazepine on viral surrogate (dsRNA)-induced TSLP and other cytokines (TNF-alpha, IL-8) in human bronchial epithelial cells (HBEC) from healthy and asthmatic donors. METHODS: HBEC obtained from healthy and asthmatic subjects were grown and stimulated with dsRNA. Cells pre-treated with Capsazepine (3-30μM), dexamethasone (0.1-10μM) or an IkappaB-kinase inhibitor (PS1145, 30μM) were also exposed to dsRNA (10μg/ml). Cells and supernatants were harvested for analyses of gene expression (RT-qPCR) and protein production (ELISA,Western blot). RESULTS: dsRNA-induced TSLP, TNF-alpha, and IL-8 in asthmatic and non-asthmatic HBEC. Dexamethasone attenuated gene expression and protein release whereas Capsazepine dose-dependently, and similar to a non-relaxant NFkB inhibitor (PS1145), completely inhibited dsRNA-induced TSLP and TNF-alpha in both healthy and asthmatic HBEC. Capsazepine reduced dsRNA-induced IL-8 and it prevented dsRNA-induced loss of the NF-κB repressor protein IkBα. CONCLUSION: Additional to its human small airway relaxant effects we now demonstrate that Capsazepine has potent anti-inflammatory effects on viral stimulus-induced cytokines in HBEC from healthy as well as asthmatic donors. Based on these data we suggest that exploration of structure-activity amongst the multifaceted capsazepinoids is warranted in search for compounds of therapeutic value in viral-induced, steroid-resistant asthma. (Less)