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Meis S, Hamacher A, Hongwiset D, Marzian C, Wiese M, Eckstein N, Royer HD, Communi D, Boeynaems JM, Hausmann R, Schmalzing G, Kassack MU: NF546 [4,4'-(carbonylbis (imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenyle ne)-carbonylimino))-bis (1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] is a non-nucleotide P2Y11 agonist and stimulates release of interleukin-8 from human monocyte-derived dendritic cells. J Pharmacol Exp Ther. 2010 Jan;332(1):238-47. Epub 2009 Oct 8.
The G protein-coupled P2Y (11) receptor is involved in immune system modulation. In-depth physiological evaluation is hampered, however, by a lack of selective and potent ligands. By screening a library of sulfonic and phosphonic acid derivatives at P2Y (11) receptors recombinantly expressed in human 1321N1 astrocytoma cells (calcium and cAMP assays), the selective non-nucleotide P2Y (11) agonist NF546 [4,4'-(carbonylbis (imino-3,1-phenylene-carbonylimino-3,1-(4-methyl-phenyle ne) carbonylimino))-bis (1,3-xylene-alpha,alpha'-diphosphonic acid) tetrasodium salt] was identified. NF546 had a pEC (50) of 6.27 and is relatively selective for P2Y (11) over P2Y (1), P2Y (2), P2Y (4), P2Y (6), P2Y (12), P2X (1), P2X (2), and P2X (2)-X (3). Adenosine-5'-O-(3-thio) triphosphate (ATPgammaS), a nonhydrolyzable analog of the physiological P2Y (11) agonist ATP, and NF546 use a common binding site as suggested by molecular modeling studies and their competitive behavior toward the nanomolar potency antagonist NF340 [4,4'-(carbonylbis (imino-3,1-(4-methyl-phenylene) carbonylimino)) bis (naphth alene-2,6-disulfonic acid) tetrasodium salt] in Schild analysis. The pA (2) of NF340 was 8.02 against ATPgammaS and 8.04 against NF546 (calcium assays). NF546 was further tested for P2Y (11)-mediated effects in monocyte-derived dendritic cells. Similarly to ATPgammaS, NF546 led to thrombospondin-1 secretion and inhibition of lipopolysaccharide-stimulated interleukin-12 release, whereas NF340 inhibited these effects. Further, for the first time, it was shown that ATPgammaS or NF546 stimulation promotes interleukin 8 (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 P2Y (11) receptors in both recombinant and physiological expression systems and could show a P2Y (11)-stimulated IL-8 release, further supporting the immunomodulatory role of P2Y (11) receptors. |
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