Ionotropic (ligand-gated ion channel), P2X, and metabotropic P2Y receptors belong to P2 receptors. Up to now, eight subtypes of human P2Y receptors are P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11-14. P2 receptors play important roles in diverse (patho)-physiological processes; for example, in the immune system, platelet aggregation, neurotransmission, oncology, and inflammation and pain. ATP inhibits tumor necrosis factor-αrelease via activation of P2Y11 receptors. P2Y11 receptors mediate ATP-induced semi-maturation of monocyte-derived dendritic cells. However, ATP effects on monocyte-derived dendritic cells. Multiple P2Y receptors mediate the cells, meanwhile, they also include effects of ADP as the ATP degradation product. P2Y11 receptors furthermore play a role in the ATP-mediated inhibition of neutrophil apoptosis. Thus, specific targeting of P2Y11 receptors could reduce neutrophil-mediated inflammatory processes. NF546 is a selective non-nucleotide P2Y11 agonist (pEC50=6.27).
ATP is the endogenous ligand at P2Y11 receptors. In this study, NF546 is a now-available selective P2Y11 ligand. Furthermore, it is a P2Y11 agonist and stimulates the release of interleukin-8 from human monocyte-derived dendritic cells. In addition, NF546 has an advantage over these ATP derivatives, because NF546 can be chemically modified, similarly to the antiviral drug Tenofovir, to become bioavailable. NF546 is relatively selective for P2Y11 over P2Y1, P2Y2, P2Y4, P2Y6, P2Y12, P2X1, P2X2, and P2X2-X3. Moreover, NF546 is equi-efficacious in stimulating TSP-1 release and inhibiting the LPS-induced release of IL-12p70 in human monocyte-derived dendritic cells. It allows in-depth physiological evaluation of the role of the P2Y11 receptors,
In summary, NF546 is a selective P2Y11 ligand and agonist. It will be helpful in further exploration of the physiological role of P2Y11 receptors.
Meis S, et al. J Pharmacol Exp Ther. 2010 Jan;332(1):238-47.