@article {Meisjpet.109.157750, author = {Sabine Meis and Alexandra Hamacher and Darunee Hongwiset and Claudia Marzian and Michael Wiese and Niels Eckstein and Hans-Dieter Royer and Didier Communi and Jean-Marie Boeynaems and Ralf Hausmann and Gunther Schmalzing and Matthias U. Kassack}, title = {NF546 [4,4{\textquoteright}-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1 (4-methyl-phenylene)-carbonylimino))-bis(1,3-xylene-α,α{\textquoteright}-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of IL-8 from human monocyte-derived dend{\textellipsis}}, elocation-id = {jpet.109.157750}, year = {2009}, doi = {10.1124/jpet.109.157750}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textquoteright}-(carbonylbis(imino-3,1-phenylene-carbonylimino-3,1 (4-methyl-phenylene)carbonylimino))-bis(1,3-xylene-α,α{\textquoteright}-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{\textquoteright}-(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}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/early/2009/10/08/jpet.109.157750}, eprint = {https://jpet.aspetjournals.org/content/early/2009/10/08/jpet.109.157750.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }