Since the cloning of the vanilloid receptor protein (TRPV1) by Caterina et al.,[1] this ligand gated nonselective cation channel has attracted growing interest due to its function associated with nociception signaling pathway. TRPV1 is activated by vanilloid ligands such as capsaicin and resiniferatoxin, noxious heat (> 42 °C), protons (extracellular pH < 6), and modulated by a variety of endogenous ligands including cannabinoid anandamide and arachidonic acid metabolites. TRPV1 activation enhances Ca2+ permeability that leads to an increase in intracellular Ca2+, resulting in excitation of primary sensory neurons and the central perception of pain. Activation is followed by the desensitization making the C-fiber sensory neurons unresponsive to TRPV1 agonists and other inflammatory mediators. In addition, capsazepine, the first reported antagonist of TRPV1, blocks the capsaicin-induced uptake of Ca2+ in cell-based assays. In vivo, capsazepine demonstrates species-dependent efficacies in various models of inflammatory hyperalgesia and chronic pain. [2] Therefore, both desensitization by an agonist and the direct blockade by an antagonist of TRPV1 might have therapeutic utility in the management of acute and chronic nociceptive pain. [3] Recently, a variety of TRPV1 ligands bearing a heterocyclic linker has been reported to show very interesting both in vitro and in vivo biological profiles. Based on these findings, we designed a series of pyrazole-based carboxamide analogues (Figure 1), assuming that the rigid heterocyclic linkage can induce more appropriate conformation for TRPV1 binding. figure 1 In this communication, we describe the synthesis and activities of a series of these ligands, which were screened by a cell-based assay utilizing the Ca2+ permeability of the TRPV1 channel. references 1. Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. Nature 1997, 387, 816–824. 2. Walker, K. M.; Urban, L.; Medhurst, S. J.; Patel, S.; Panesar, M.; Fox, A. J. J. Pharmacol. Exp. Ther. 2003, 304, 56-62. 3. De Petrocellis, L.; Schiano-Moriello A. Recent Pat. CNS Drug Discov. 2013, 8, 180-204 Synthesis and evaluation of new pyrazole-based carboxamides as modulators of the TRPV1 channel Cenzo Congiu,1* Valentina Onnis,1 Marco Allarà,2 Aniello Schiano-Moriello,2 Vincenzo Di Marzo,2 and Luciano De Petrocellis.2 1University of Cagliari, Department of Life and Environment Sciences, Via Ospedale 72, I-09124 – Cagliari, Italy; 2Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, I-80078-Pozzuoli (NA), Italy Since the cloning of the vanilloid receptor protein (TRPV1) by Caterina et al.,[1] this ligand gated nonselective cation channel has attracted growing interest due to its function associated with nociception signaling pathway. TRPV1 is activated by vanilloid ligands such as capsaicin and resiniferatoxin, noxious heat (> 42 °C), protons (extracellular pH < 6), and modulated by a variety of endogenous ligands including cannabinoid anandamide and arachidonic acid metabolites. TRPV1 activation enhances Ca2+ permeability that leads to an increase in intracellular Ca2+, resulting in excitation of primary sensory neurons and the central perception of pain. Activation is followed by the desensitization making the C-fiber sensory neurons unresponsive to TRPV1 agonists and other inflammatory mediators. In addition, capsazepine, the first reported antagonist of TRPV1, blocks the capsaicin-induced uptake of Ca2+ in cell-based assays. In vivo, capsazepine demonstrates species-dependent efficacies in various models of inflammatory hyperalgesia and chronic pain.[2] Therefore, both desensitization by an agonist and the direct blockade by an antagonist of TRPV1 might have therapeutic utility in the management of acute and chronic nociceptive pain.[3] Recently, a variety of TRPV1 ligands bearing a heterocyclic linker has been reported to show very interesting both in vitro and in vivo biological profiles. Based on these findings, we designed a series of pyrazole-based carboxamide analogues (Figure 1), assuming that the rigid heterocyclic linkage can induce more appropriate conformation for

Synthesis and evaluation of new pyrazole-based carboxamides as modulators of the TrPv1 channel

CONGIU, CENZO;
2015

Abstract

Since the cloning of the vanilloid receptor protein (TRPV1) by Caterina et al.,[1] this ligand gated nonselective cation channel has attracted growing interest due to its function associated with nociception signaling pathway. TRPV1 is activated by vanilloid ligands such as capsaicin and resiniferatoxin, noxious heat (> 42 °C), protons (extracellular pH < 6), and modulated by a variety of endogenous ligands including cannabinoid anandamide and arachidonic acid metabolites. TRPV1 activation enhances Ca2+ permeability that leads to an increase in intracellular Ca2+, resulting in excitation of primary sensory neurons and the central perception of pain. Activation is followed by the desensitization making the C-fiber sensory neurons unresponsive to TRPV1 agonists and other inflammatory mediators. In addition, capsazepine, the first reported antagonist of TRPV1, blocks the capsaicin-induced uptake of Ca2+ in cell-based assays. In vivo, capsazepine demonstrates species-dependent efficacies in various models of inflammatory hyperalgesia and chronic pain. [2] Therefore, both desensitization by an agonist and the direct blockade by an antagonist of TRPV1 might have therapeutic utility in the management of acute and chronic nociceptive pain. [3] Recently, a variety of TRPV1 ligands bearing a heterocyclic linker has been reported to show very interesting both in vitro and in vivo biological profiles. Based on these findings, we designed a series of pyrazole-based carboxamide analogues (Figure 1), assuming that the rigid heterocyclic linkage can induce more appropriate conformation for TRPV1 binding. figure 1 In this communication, we describe the synthesis and activities of a series of these ligands, which were screened by a cell-based assay utilizing the Ca2+ permeability of the TRPV1 channel. references 1. Caterina, M. J.; Schumacher, M. A.; Tominaga, M.; Rosen, T. A.; Levine, J. D.; Julius, D. Nature 1997, 387, 816–824. 2. Walker, K. M.; Urban, L.; Medhurst, S. J.; Patel, S.; Panesar, M.; Fox, A. J. J. Pharmacol. Exp. Ther. 2003, 304, 56-62. 3. De Petrocellis, L.; Schiano-Moriello A. Recent Pat. CNS Drug Discov. 2013, 8, 180-204 Synthesis and evaluation of new pyrazole-based carboxamides as modulators of the TRPV1 channel Cenzo Congiu,1* Valentina Onnis,1 Marco Allarà,2 Aniello Schiano-Moriello,2 Vincenzo Di Marzo,2 and Luciano De Petrocellis.2 1University of Cagliari, Department of Life and Environment Sciences, Via Ospedale 72, I-09124 – Cagliari, Italy; 2Endocannabinoid Research Group (ERG), Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, I-80078-Pozzuoli (NA), Italy Since the cloning of the vanilloid receptor protein (TRPV1) by Caterina et al.,[1] this ligand gated nonselective cation channel has attracted growing interest due to its function associated with nociception signaling pathway. TRPV1 is activated by vanilloid ligands such as capsaicin and resiniferatoxin, noxious heat (> 42 °C), protons (extracellular pH < 6), and modulated by a variety of endogenous ligands including cannabinoid anandamide and arachidonic acid metabolites. TRPV1 activation enhances Ca2+ permeability that leads to an increase in intracellular Ca2+, resulting in excitation of primary sensory neurons and the central perception of pain. Activation is followed by the desensitization making the C-fiber sensory neurons unresponsive to TRPV1 agonists and other inflammatory mediators. In addition, capsazepine, the first reported antagonist of TRPV1, blocks the capsaicin-induced uptake of Ca2+ in cell-based assays. In vivo, capsazepine demonstrates species-dependent efficacies in various models of inflammatory hyperalgesia and chronic pain.[2] Therefore, both desensitization by an agonist and the direct blockade by an antagonist of TRPV1 might have therapeutic utility in the management of acute and chronic nociceptive pain.[3] Recently, a variety of TRPV1 ligands bearing a heterocyclic linker has been reported to show very interesting both in vitro and in vivo biological profiles. Based on these findings, we designed a series of pyrazole-based carboxamide analogues (Figure 1), assuming that the rigid heterocyclic linkage can induce more appropriate conformation for
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