RT Journal Article
SR Electronic
T1 NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1 (4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-α,α'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y<sub>11</sub> agonist and stimulates release of IL-8 from human monocyte-derived dendritic cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.109.157750
DO 10.1124/jpet.109.157750
A1 Sabine Meis
A1 Alexandra Hamacher
A1 Darunee Hongwiset
A1 Claudia Marzian
A1 Michael Wiese
A1 Niels Eckstein
A1 Hans-Dieter Royer
A1 Didier Communi
A1 Jean-Marie Boeynaems
A1 Ralf Hausmann
A1 Gunther Schmalzing
A1 Matthias U. Kassack
YR 2009
UL http://jpet.aspetjournals.org/content/early/2009/10/08/jpet.109.157750.abstract
AB The G protein-coupled P2Y11 receptor is involved in immune system modulation. In depth physiological evaluation is however hampered by a lack of selective and potent ligands. By screening a library of sulfonic and phosphonic acid derivatives at P2Y11 receptors recombinantly expressed in human 1321N1 astrocytoma cells (calcium and cAMP assays), the selective non-nucleotide P2Y11 agonist NF546 [4,4'-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1 (4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-α,α'-diphosphonic acid) tetrasodium salt]was identified. NF546 had a pEC50 of 6.27 and is relatively selective for P2Y11 over P2Y1, P2Y2, P2Y4, P2Y6, P2Y12, P2X1, P2X2, and P2X2-X3. ATPγS, a non-hydrolysable analogue of the physiological P2Y11 agonist ATP, and NF546 use a common binding site as suggested by molecular modelling studies and their competitive behaviour towards the nanomolar potency antagonist NF340 [4,4'-(carbonylbis(imino-3,1-(4 methyl-phenylene)carbonylimino))bis(naphthalene-2,6-disulfonic acid) tetrasodium salt] in Schild analysis. The pA2 of NF340 was 8.02 against ATPγS and 8.04 against NF546 (calcium assays). NF546 was further tested for P2Y11-mediated effects in monocyte-derived dendritic cells. Equal to ATPγS, NF546 led to thrombospondin-1 secretion and inhibition of LPS-stimulated IL-12 release, whereas NF340 inhibited these effects. It was further shown for the first time that ATPγS or NF546 stimulation promotes IL-8 release from dendritic cells which could be inhibited by NF340. In conclusion, we have described the first selective, non-nucleotide agonist NF546 for P2Y11 receptors in both, recombinant and physiological expression systems and could show a P2Y11-stimulated IL-8 release further supporting an immunomodulatory role of P2Y11 receptors.The American Society for Pharmacology and Experimental Therapeutics