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Basil D. Roufogalis - One of the best experts on this subject based on the ideXlab platform.
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Gingerols: a novel class of Vanilloid Receptor (VR1) agonists
2002Co-Authors: Vadim N. Dedov, Van H. Tran, Colin C. Duke, Mark Connor, Macdonald J. Christie, Sravan Mandadi, Basil D. RoufogalisAbstract:Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin-activated VR1 (Vanilloid) Receptor. [6]-Gingerol and [8]-gingerol evoked capsaicin-like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 Receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 Receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 Receptor. Keywords: Ginger, gingerols, DRG neurones, VR1 Receptor, intracellular calcium, plasma membrane currents Introduction Ginger (Zingiber officinale) has been used extensively for more than 2500 years in China for conditions including headaches, nausea and colds (Grant & Lutz, 2000) and in Ayurvedic (Sharma & Clark, 1998) and Western herbal medicine practice for the treatment of arthritis, rheumatological conditions and muscular discomfort (Blumenthal & Werner, 1998). Its use in inflammatory conditions is consistent with anti-inflammatory activities of its components in vitro (Kiuchi et al., 1982; Mascolo et al., 1989). The moderate pungency of ginger has been attributed to the mixture of gingerol derivatives in the oleoresin fraction of processed ginger (Mustafa et al., 1993). Gingerols possess the vanillyl moiety (Figure 1, region A), which is considered important for activation of the VR1 Receptor expressed in nociceptive sensory neurones (Walpole et al., 1993a). Recently it was found that molecules lacking the vanillyl structure also activate the VR1 Receptor in DRG neurones. These molecules include N-arachidonoyl-dopamine and its 3-O-methyl analogue (Huang et al., 2002), anandamide, an endogenous ligand of the neuronal cannabinoid Receptor (CB1) (Smart & Jerman, 2000; Smart et al., 2000; Zygmunt et al., 1999), lipoxygenase metabolites (Hwang et al., 2000; Craib et al., 2001; Piomelli, 2001), and the naturally occurring sesquiterpene dialdehydes (Szallasi et al., 1998). The VR1 Receptor has recently been cloned and suggested to integrate chemical and thermal nociceptive stimuli (Tominaga et al., 1998; Caterina et al., 1997; 2000). Therefore, direct activation/deactivation of the VR1 Receptor at the site where pain is generated during inflammation and other painful conditions provides a new strategy for the development of a new class of peripheral analgesics devoid of the well characterized side effects of currently available analgesics (Kress & Zeilhofer, 1999; Roufogalis & Dedov, 1999). Furthermore, VR1-expressing neurones have recently been found throughout the whole neuroaxis (Mezey et al., 2000), opening up a new and so far unexplored area of VR1-related drug development. We report here for the first time to our knowledge that the pungent principle of ginger, [6]-gingerol and [8]-gingerol, activate the VR1 Receptor in capsaicin-sensitive neurones and that activation is blocked by the VR1 antagonist, capsazepine. Figure 1 Comparison of capsaicin, [6]-gingerol, [8]-gingerol and zingerone. The molecules are divided into ‘A', ‘B' and ‘C' regions, as described for capsaicin by Walpole et al. (1993a, 1993b, 1993c). Log ... Methods Materials Fura-2 and Fluo-4 were obtained from Molecular Probes Inc. (Eugene, U.S.A.), DMEM and Neurobasal medium were from GIBCO (Gaithersburg, U.S.A.), NGF from ICN Biochemicals (Costa Mesa, U.S.A.). Other agents were obtained from Sigma (St. Louis, U.S.A.). All reagents were of analytical grade. Racemic [6]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one) and [8]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one) were prepared as described in the literature (Denniff et al., 1981). Log P values of the compounds were calculated using Molecular Modeling Pro software (ChemSW, version 3.23).
Vadim N. Dedov - One of the best experts on this subject based on the ideXlab platform.
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Gingerols: a novel class of Vanilloid Receptor (VR1) agonists
2002Co-Authors: Vadim N. Dedov, Van H. Tran, Colin C. Duke, Mark Connor, Macdonald J. Christie, Sravan Mandadi, Basil D. RoufogalisAbstract:Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin-activated VR1 (Vanilloid) Receptor. [6]-Gingerol and [8]-gingerol evoked capsaicin-like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 Receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 Receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 Receptor. Keywords: Ginger, gingerols, DRG neurones, VR1 Receptor, intracellular calcium, plasma membrane currents Introduction Ginger (Zingiber officinale) has been used extensively for more than 2500 years in China for conditions including headaches, nausea and colds (Grant & Lutz, 2000) and in Ayurvedic (Sharma & Clark, 1998) and Western herbal medicine practice for the treatment of arthritis, rheumatological conditions and muscular discomfort (Blumenthal & Werner, 1998). Its use in inflammatory conditions is consistent with anti-inflammatory activities of its components in vitro (Kiuchi et al., 1982; Mascolo et al., 1989). The moderate pungency of ginger has been attributed to the mixture of gingerol derivatives in the oleoresin fraction of processed ginger (Mustafa et al., 1993). Gingerols possess the vanillyl moiety (Figure 1, region A), which is considered important for activation of the VR1 Receptor expressed in nociceptive sensory neurones (Walpole et al., 1993a). Recently it was found that molecules lacking the vanillyl structure also activate the VR1 Receptor in DRG neurones. These molecules include N-arachidonoyl-dopamine and its 3-O-methyl analogue (Huang et al., 2002), anandamide, an endogenous ligand of the neuronal cannabinoid Receptor (CB1) (Smart & Jerman, 2000; Smart et al., 2000; Zygmunt et al., 1999), lipoxygenase metabolites (Hwang et al., 2000; Craib et al., 2001; Piomelli, 2001), and the naturally occurring sesquiterpene dialdehydes (Szallasi et al., 1998). The VR1 Receptor has recently been cloned and suggested to integrate chemical and thermal nociceptive stimuli (Tominaga et al., 1998; Caterina et al., 1997; 2000). Therefore, direct activation/deactivation of the VR1 Receptor at the site where pain is generated during inflammation and other painful conditions provides a new strategy for the development of a new class of peripheral analgesics devoid of the well characterized side effects of currently available analgesics (Kress & Zeilhofer, 1999; Roufogalis & Dedov, 1999). Furthermore, VR1-expressing neurones have recently been found throughout the whole neuroaxis (Mezey et al., 2000), opening up a new and so far unexplored area of VR1-related drug development. We report here for the first time to our knowledge that the pungent principle of ginger, [6]-gingerol and [8]-gingerol, activate the VR1 Receptor in capsaicin-sensitive neurones and that activation is blocked by the VR1 antagonist, capsazepine. Figure 1 Comparison of capsaicin, [6]-gingerol, [8]-gingerol and zingerone. The molecules are divided into ‘A', ‘B' and ‘C' regions, as described for capsaicin by Walpole et al. (1993a, 1993b, 1993c). Log ... Methods Materials Fura-2 and Fluo-4 were obtained from Molecular Probes Inc. (Eugene, U.S.A.), DMEM and Neurobasal medium were from GIBCO (Gaithersburg, U.S.A.), NGF from ICN Biochemicals (Costa Mesa, U.S.A.). Other agents were obtained from Sigma (St. Louis, U.S.A.). All reagents were of analytical grade. Racemic [6]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one) and [8]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one) were prepared as described in the literature (Denniff et al., 1981). Log P values of the compounds were calculated using Molecular Modeling Pro software (ChemSW, version 3.23).
Van H. Tran - One of the best experts on this subject based on the ideXlab platform.
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Gingerols: a novel class of Vanilloid Receptor (VR1) agonists
2002Co-Authors: Vadim N. Dedov, Van H. Tran, Colin C. Duke, Mark Connor, Macdonald J. Christie, Sravan Mandadi, Basil D. RoufogalisAbstract:Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin-activated VR1 (Vanilloid) Receptor. [6]-Gingerol and [8]-gingerol evoked capsaicin-like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 Receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 Receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 Receptor. Keywords: Ginger, gingerols, DRG neurones, VR1 Receptor, intracellular calcium, plasma membrane currents Introduction Ginger (Zingiber officinale) has been used extensively for more than 2500 years in China for conditions including headaches, nausea and colds (Grant & Lutz, 2000) and in Ayurvedic (Sharma & Clark, 1998) and Western herbal medicine practice for the treatment of arthritis, rheumatological conditions and muscular discomfort (Blumenthal & Werner, 1998). Its use in inflammatory conditions is consistent with anti-inflammatory activities of its components in vitro (Kiuchi et al., 1982; Mascolo et al., 1989). The moderate pungency of ginger has been attributed to the mixture of gingerol derivatives in the oleoresin fraction of processed ginger (Mustafa et al., 1993). Gingerols possess the vanillyl moiety (Figure 1, region A), which is considered important for activation of the VR1 Receptor expressed in nociceptive sensory neurones (Walpole et al., 1993a). Recently it was found that molecules lacking the vanillyl structure also activate the VR1 Receptor in DRG neurones. These molecules include N-arachidonoyl-dopamine and its 3-O-methyl analogue (Huang et al., 2002), anandamide, an endogenous ligand of the neuronal cannabinoid Receptor (CB1) (Smart & Jerman, 2000; Smart et al., 2000; Zygmunt et al., 1999), lipoxygenase metabolites (Hwang et al., 2000; Craib et al., 2001; Piomelli, 2001), and the naturally occurring sesquiterpene dialdehydes (Szallasi et al., 1998). The VR1 Receptor has recently been cloned and suggested to integrate chemical and thermal nociceptive stimuli (Tominaga et al., 1998; Caterina et al., 1997; 2000). Therefore, direct activation/deactivation of the VR1 Receptor at the site where pain is generated during inflammation and other painful conditions provides a new strategy for the development of a new class of peripheral analgesics devoid of the well characterized side effects of currently available analgesics (Kress & Zeilhofer, 1999; Roufogalis & Dedov, 1999). Furthermore, VR1-expressing neurones have recently been found throughout the whole neuroaxis (Mezey et al., 2000), opening up a new and so far unexplored area of VR1-related drug development. We report here for the first time to our knowledge that the pungent principle of ginger, [6]-gingerol and [8]-gingerol, activate the VR1 Receptor in capsaicin-sensitive neurones and that activation is blocked by the VR1 antagonist, capsazepine. Figure 1 Comparison of capsaicin, [6]-gingerol, [8]-gingerol and zingerone. The molecules are divided into ‘A', ‘B' and ‘C' regions, as described for capsaicin by Walpole et al. (1993a, 1993b, 1993c). Log ... Methods Materials Fura-2 and Fluo-4 were obtained from Molecular Probes Inc. (Eugene, U.S.A.), DMEM and Neurobasal medium were from GIBCO (Gaithersburg, U.S.A.), NGF from ICN Biochemicals (Costa Mesa, U.S.A.). Other agents were obtained from Sigma (St. Louis, U.S.A.). All reagents were of analytical grade. Racemic [6]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one) and [8]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one) were prepared as described in the literature (Denniff et al., 1981). Log P values of the compounds were calculated using Molecular Modeling Pro software (ChemSW, version 3.23).
Colin C. Duke - One of the best experts on this subject based on the ideXlab platform.
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Gingerols: a novel class of Vanilloid Receptor (VR1) agonists
2002Co-Authors: Vadim N. Dedov, Van H. Tran, Colin C. Duke, Mark Connor, Macdonald J. Christie, Sravan Mandadi, Basil D. RoufogalisAbstract:Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin-activated VR1 (Vanilloid) Receptor. [6]-Gingerol and [8]-gingerol evoked capsaicin-like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 Receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 Receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 Receptor. Keywords: Ginger, gingerols, DRG neurones, VR1 Receptor, intracellular calcium, plasma membrane currents Introduction Ginger (Zingiber officinale) has been used extensively for more than 2500 years in China for conditions including headaches, nausea and colds (Grant & Lutz, 2000) and in Ayurvedic (Sharma & Clark, 1998) and Western herbal medicine practice for the treatment of arthritis, rheumatological conditions and muscular discomfort (Blumenthal & Werner, 1998). Its use in inflammatory conditions is consistent with anti-inflammatory activities of its components in vitro (Kiuchi et al., 1982; Mascolo et al., 1989). The moderate pungency of ginger has been attributed to the mixture of gingerol derivatives in the oleoresin fraction of processed ginger (Mustafa et al., 1993). Gingerols possess the vanillyl moiety (Figure 1, region A), which is considered important for activation of the VR1 Receptor expressed in nociceptive sensory neurones (Walpole et al., 1993a). Recently it was found that molecules lacking the vanillyl structure also activate the VR1 Receptor in DRG neurones. These molecules include N-arachidonoyl-dopamine and its 3-O-methyl analogue (Huang et al., 2002), anandamide, an endogenous ligand of the neuronal cannabinoid Receptor (CB1) (Smart & Jerman, 2000; Smart et al., 2000; Zygmunt et al., 1999), lipoxygenase metabolites (Hwang et al., 2000; Craib et al., 2001; Piomelli, 2001), and the naturally occurring sesquiterpene dialdehydes (Szallasi et al., 1998). The VR1 Receptor has recently been cloned and suggested to integrate chemical and thermal nociceptive stimuli (Tominaga et al., 1998; Caterina et al., 1997; 2000). Therefore, direct activation/deactivation of the VR1 Receptor at the site where pain is generated during inflammation and other painful conditions provides a new strategy for the development of a new class of peripheral analgesics devoid of the well characterized side effects of currently available analgesics (Kress & Zeilhofer, 1999; Roufogalis & Dedov, 1999). Furthermore, VR1-expressing neurones have recently been found throughout the whole neuroaxis (Mezey et al., 2000), opening up a new and so far unexplored area of VR1-related drug development. We report here for the first time to our knowledge that the pungent principle of ginger, [6]-gingerol and [8]-gingerol, activate the VR1 Receptor in capsaicin-sensitive neurones and that activation is blocked by the VR1 antagonist, capsazepine. Figure 1 Comparison of capsaicin, [6]-gingerol, [8]-gingerol and zingerone. The molecules are divided into ‘A', ‘B' and ‘C' regions, as described for capsaicin by Walpole et al. (1993a, 1993b, 1993c). Log ... Methods Materials Fura-2 and Fluo-4 were obtained from Molecular Probes Inc. (Eugene, U.S.A.), DMEM and Neurobasal medium were from GIBCO (Gaithersburg, U.S.A.), NGF from ICN Biochemicals (Costa Mesa, U.S.A.). Other agents were obtained from Sigma (St. Louis, U.S.A.). All reagents were of analytical grade. Racemic [6]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one) and [8]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one) were prepared as described in the literature (Denniff et al., 1981). Log P values of the compounds were calculated using Molecular Modeling Pro software (ChemSW, version 3.23).
Mark Connor - One of the best experts on this subject based on the ideXlab platform.
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Gingerols: a novel class of Vanilloid Receptor (VR1) agonists
2002Co-Authors: Vadim N. Dedov, Van H. Tran, Colin C. Duke, Mark Connor, Macdonald J. Christie, Sravan Mandadi, Basil D. RoufogalisAbstract:Gingerols, the pungent constituents of ginger, were synthesized and assessed as agonists of the capsaicin-activated VR1 (Vanilloid) Receptor. [6]-Gingerol and [8]-gingerol evoked capsaicin-like intracellular Ca2+ transients and ion currents in cultured DRG neurones. These effects of gingerols were blocked by capsazepine, the VR1 Receptor antagonist. The potency of gingerols increased with increasing size of the side chain and with the overall hydrophobicity in the series. We conclude that gingerols represent a novel class of naturally occurring VR1 Receptor agonists that may contribute to the medicinal properties of ginger, which have been known for centuries. The gingerol structure may be used as a template for the development of drugs acting as moderately potent activators of the VR1 Receptor. Keywords: Ginger, gingerols, DRG neurones, VR1 Receptor, intracellular calcium, plasma membrane currents Introduction Ginger (Zingiber officinale) has been used extensively for more than 2500 years in China for conditions including headaches, nausea and colds (Grant & Lutz, 2000) and in Ayurvedic (Sharma & Clark, 1998) and Western herbal medicine practice for the treatment of arthritis, rheumatological conditions and muscular discomfort (Blumenthal & Werner, 1998). Its use in inflammatory conditions is consistent with anti-inflammatory activities of its components in vitro (Kiuchi et al., 1982; Mascolo et al., 1989). The moderate pungency of ginger has been attributed to the mixture of gingerol derivatives in the oleoresin fraction of processed ginger (Mustafa et al., 1993). Gingerols possess the vanillyl moiety (Figure 1, region A), which is considered important for activation of the VR1 Receptor expressed in nociceptive sensory neurones (Walpole et al., 1993a). Recently it was found that molecules lacking the vanillyl structure also activate the VR1 Receptor in DRG neurones. These molecules include N-arachidonoyl-dopamine and its 3-O-methyl analogue (Huang et al., 2002), anandamide, an endogenous ligand of the neuronal cannabinoid Receptor (CB1) (Smart & Jerman, 2000; Smart et al., 2000; Zygmunt et al., 1999), lipoxygenase metabolites (Hwang et al., 2000; Craib et al., 2001; Piomelli, 2001), and the naturally occurring sesquiterpene dialdehydes (Szallasi et al., 1998). The VR1 Receptor has recently been cloned and suggested to integrate chemical and thermal nociceptive stimuli (Tominaga et al., 1998; Caterina et al., 1997; 2000). Therefore, direct activation/deactivation of the VR1 Receptor at the site where pain is generated during inflammation and other painful conditions provides a new strategy for the development of a new class of peripheral analgesics devoid of the well characterized side effects of currently available analgesics (Kress & Zeilhofer, 1999; Roufogalis & Dedov, 1999). Furthermore, VR1-expressing neurones have recently been found throughout the whole neuroaxis (Mezey et al., 2000), opening up a new and so far unexplored area of VR1-related drug development. We report here for the first time to our knowledge that the pungent principle of ginger, [6]-gingerol and [8]-gingerol, activate the VR1 Receptor in capsaicin-sensitive neurones and that activation is blocked by the VR1 antagonist, capsazepine. Figure 1 Comparison of capsaicin, [6]-gingerol, [8]-gingerol and zingerone. The molecules are divided into ‘A', ‘B' and ‘C' regions, as described for capsaicin by Walpole et al. (1993a, 1993b, 1993c). Log ... Methods Materials Fura-2 and Fluo-4 were obtained from Molecular Probes Inc. (Eugene, U.S.A.), DMEM and Neurobasal medium were from GIBCO (Gaithersburg, U.S.A.), NGF from ICN Biochemicals (Costa Mesa, U.S.A.). Other agents were obtained from Sigma (St. Louis, U.S.A.). All reagents were of analytical grade. Racemic [6]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)decan-3-one) and [8]-gingerol (5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecan-3-one) were prepared as described in the literature (Denniff et al., 1981). Log P values of the compounds were calculated using Molecular Modeling Pro software (ChemSW, version 3.23).
