title: [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.
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<0.05). These data demonstrate that A-804598 is one of the most potent and selective antagonists for mammalian P2X7 receptors described to date and [3H]A-804598 is a high affinity antagonist radioligand that specifically labels rat P2X7 receptors.
authors.affiliation: Neuroscience Research, Abbott Laboratories, 100 Abbott Park Road, Building. AP9A, Department R4PM, Abbott Park, IL 60064-6123, USA.
authors.forename: Diana L
authors.initials: DL
authors.lastname: Donnelly-Roberts
authors.forename: Marian T
authors.initials: MT
authors.lastname: Namovic
authors.forename: Bruce
authors.initials: B
authors.lastname: Surber
authors.forename: Srirajan X
authors.initials: SX
authors.lastname: Vaidyanathan
authors.forename: Arturo
authors.initials: A
authors.lastname: Perez-Medrano
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D001254:Astrocytoma; D001583:Benzoxazoles / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D014162:Transfection; D014316:Tritium / Q000494:pharmacology
chemical_list: C539459:2-cyano-1-((1S)-1-phenylethyl)-3-quinolin-5-ylguanidine; D001583:Benzoxazoles; D006146:Guanidines; D053583:Interleukin-1beta; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; C546470:P2rx7 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D011804:Quinolines; D011806:Quinolinium Compounds; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D014316:Tritium; C089813:YO-PRO 1; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D002118:Calcium