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[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
- Source :
- Neuropharmacology. 56:223-229
- Publication Year :
- 2009
- Publisher :
- Elsevier BV, 2009.
-
Abstract
- 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
- Subjects :
- 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
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 56
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....5d06b223047cee3eda2d5057a68ebe4a