1,721,335 research outputs found
Synthesis and evaluation of new pyrazole-based carboxamides as modulators of the TrPv1 channel
No full textSince 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 fo
Evidences on arginine-lysine side chains interaction for the formation aggregational states of the H1 histone
No full textActions and Regulation of Ionotropic Cannabinoid Receptors
No full textPreparations of the Cannabis plant have been used by man for multiple
purposes for millennia; however, a pharmacological understanding of the
plant’s unique metabolites has only come about in the last 60–70 years.
A key landmark in cannabinoid science was the work of Raphael
Mechoulam identifying the nature of many of these unique metabolites,
notably Δ9-tetrahydrocannabinol (THC) in the early 1960s. In the late
1980s, William Devane and Allyn Howlett provided evidence for the existence
of a cannabinoid receptor in the brain, where THC predominantly
acts. Molecular identification of this CB1 cannabinoid receptor and a
“peripheral” CB2 cannabinoid receptor was reported in the early 1990s
by Tom Bonner and Sean Munro, respectively. At about that time, Raphael
Mechoulam and Roger Pertwee expanded the field further with identification
of the two major endogenous agonists at the cannabinoid receptors,
paving the way for characterization of the multiple constituents of the
endocannabinoid system.
Today, a simple interrogation of PubMed reveals tens of thousands of
published articles relating to Cannabis and the cannabinoids.
The breadth of involvement of cannabinoids and their receptors in
basic physiology and pathophysiology is immense ranging from roles in
the most basic aspects of gene expression to suspected mediation of complex
disease processes including chronic pain, cancer, schizophrenia, and
neurodegeneration.
Getting to grips with such a massive and diverse subject requires some
signposting and the Pharmacology of Cannabinoids aims to do just that. The
chapters are authored by combinations of experienced and well-published
experts in the field who have not, in the main, worked together previously,
a strategy which we think facilitates fresh approaches to the topics covered.
The scene is set with reviews of the pharmacology of the plant-derived
cannabinoids and the diverse range of endogenous lipids that underpin
cannabinoid signaling in the body. How these endocannabinoids are practically
analyzed and quantified is also explained, as well as descriptions of the
mechanisms of their turnover. The multiple targets for the endogenous and
exogenous cannabinoids are discussed in chapters covering the G proteincoupled
CB1 and CB2 receptors, cannabinoid-receptor-like orphan GPCR,
ion channels (particularly the transient receptor potential channels), and nuclear receptors; postreceptor signaling mechanisms are described within
these chapters. It is now clear that agonist signaling in general is more
dynamic than previously thought and a chapter on cannabinoid agonist bias
is included.
Understanding the roles of cannabinoids in the pathophysiology of
important disease states and the potential for developing new therapies based
on an expanded knowledge base is crucial and chapters are devoted to
in-depth accounts of cannabinoid involvement in pain, cancer, and cardiovascular
and neuroinflammatory diseases.
We are sincerely grateful to our friends and colleagues who have contributed
to this volume which we trust will be a useful reference source
and, hopefully, an inspiration to scientists, be they novices in the field or
cannabinoid aficionados
Anion-mediated lysine-arginine interaction.Evidence in Chaetopterus variopedatus sperm protamine
No full text
Anion-mediated lysine-arginine interaction.Evidence in Chaetopterus variopedatus sperm protamine
No full text- …
