[3H]A-804598 ([3H]2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine) is a novel, potent, and selective antagonist radioligand for P2X7 receptors
| Autor: | Arturo Perez-Medrano, William A. Carroll, Diana L. Donnelly-Roberts, Srirajan Vaidyanathan, Bruce Surber, Michael F. Jarvis, Marian T. Namovic, Ying Wang |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
medicine.drug_class Interleukin-1beta Astrocytoma Transfection Tritium Binding Competitive Guanidines KN-62 Inhibitory Concentration 50 Mice Radioligand Assay Cellular and Molecular Neuroscience chemistry.chemical_compound Adenosine Triphosphate Cell Line Tumor Purinergic P2 Receptor Antagonists medicine Radioligand Animals Humans PPADS Receptor IC50 Pharmacology Benzoxazoles Dose-Response Relationship Drug Receptors Purinergic P2 Quinolinium Compounds Cell Membrane Antagonist Molecular biology Recombinant Proteins Rats chemistry Biochemistry Quinolines Calcium Receptors Purinergic P2X7 |
| Zdroj: | Neuropharmacology. 56:223-229 |
| ISSN: | 0028-3908 |
| Popis: | ATP-sensitive P2X7 receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X7 receptors leads to rapid changes in intracellular calcium concentrations, release of the pro-inflammatory cytokine IL-1beta, and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Data from gene knockout studies and recently described selective antagonists indicate a role for P2X7 receptor activation in inflammation and pain. While several species selective P2X7 antagonists exist, A-804598 represents a structurally novel, competitive, and selective antagonist that has equivalent high affinity at rat (IC50 = 10 nM), mouse (IC50 = 9 nM) and human (IC50 = 11 nM) P2X7 receptors. A-804598 also potently blocked agonist stimulated release of IL-1beta and Yo-Pro uptake from differentiated THP-1 cells that natively express human P2X7 receptors. A-804598 was tritiated ([3H]A-804598; 8.1Ci/mmol) and utilized to study recombinant rat P2X7 receptors expressed in 1321N1 cells. [3H]A-804598 labeled a single class of high affinity binding sites (Kd=2.4 nM and apparent Bmax=0.56 pmol/mg). No specific binding was observed in untransfected 1321N1 cells. The pharmacological profile for P2X antagonists to inhibit [3H]A-804598 binding correlated with their ability to block functional activation of P2X7 receptors (r=0.95, P |
| Databáze: | OpenAIRE |
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