MRS 2578

MRS 2578 is a potent and insurmountable antagonist of P2Y6 nucleotide receptor with IC50 value of 37nM [1].

MRS 2578, a diisothiocyanate derivative, is an insurmountable antagonist of P2Y6 receptors which are associated with vasoconstriction. Thus MRS 2578 is expected to be used in treatment of vasospasm. In 1321N1 human astrocytes expressing P2Y6 receptors, MRS 2578 inhibits the UDP-induced accumulation of inositol phosphates in a dose-dependent manner. MRS 2578 also inhibits the rat P2Y6 receptor activation with IC50 value of 98nM. These effects are selective. MRS 2578 has no effect on the UTP-induced responses of cells expressing human P2Y2 or P2Y4 receptors. It also has no effect on the 2-MeSADP-induced responses of cells expressing the P2Y1 receptor. Moreover, since the UDP-induced activation of P2Y6 receptor can protect the cells from apoptosis induced by TNFα, MRS 2578 completely blocks the protection of cells [1].

References:
[1] Mamedova L K, Joshi B V, Gao Z G, et al. Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors[J]. Biochemical pharmacology, 2004, 67(9): 1763-1770.

Characterization of UDP-Activated Purinergic Receptor P2Y(6) Involved in Japanese Flounder Paralichthys olivaceus Innate Immunity.[Pubmed:30029501]

Int J Mol Sci. 2018 Jul 19;19(7). pii: ijms19072095.

Uridine 5'-diphosphate (UDP)-activated purinergic receptor P2Y(6) is a member of a G-protein-coupled purinergic receptor family that plays an important role in mammalian innate immunity. However, the role of the P2Y(6) receptor (P2Y(6)R) in fish immunity has not been investigated. In this report, we characterized a P2Y(6)R gene from Japanese flounder (Paralichthys olivaceus) and examined its role in fish innate immunity. Sequence analysis reveals that the Japanese flounder P2Y(6)R protein is conserved and possesses four potential glycosylation sites. Quantitative real-time RT-PCR analysis shows that P2Y(6)R is broadly distributed in all examined Japanese flounder tissues with dominant expression in the liver. In addition, P2Y(6)R gene expression was up-regulated in head kidney macrophages (HKMs) upon lipopolysaccharides (LPS) and poly(I:C) stimulations but down-regulated by LPS challenge in peripheral blood leukocytes (PBLs). Furthermore, pharmacological inhibition of the endogenous P2Y(6) receptor activity by the potently selective P2Y(6)R antagonist, MRS 2578, greatly up-regulated pro-inflammatory cytokine interleukin (IL)-1beta, IL-6 and TNF-alpha gene expression in PBL cells treated with UDP. Moreover, LPS- and poly(I:C)-induced gene expression of IL-1beta and TNF-alpha in Japanese flounder PBL cells was attenuated significantly by inhibition of P2Y(6)R activity with antagonist MRS 2578. Collectively, we, for the first time, showed the involvement of functional purinergic P2Y(6)R in fish innate immunity.

Thymidine 5'-O-monophosphorothioate induces HeLa cell migration by activation of the P2Y6 receptor.[Pubmed:26746211]

Purinergic Signal. 2016 Jun;12(2):199-209.

ATP, ADP, UTP, and UDP acting as ligands of specific P2Y receptors activate intracellular signaling cascades to regulate a variety of cellular processes, including proliferation, migration, differentiation, and cell death. Contrary to a widely held opinion, we show here that nucleoside 5'-O-monophosphorothioate analogs, containing a sulfur atom in a place of one nonbridging oxygen atom in a phosphate group, act as ligands for selected P2Y subtypes. We pay particular attention to the unique activity of thymidine 5'-O-monophosphorothioate (TMPS) which acts as a specific partial agonist of the P2Y6 receptor (P2Y6R). We also collected evidence for the involvement of the P2Y6 receptor in human epithelial adenocarcinoma cell line (HeLa) cell migration induced by thymidine 5'-O-monophosphorothioate analog. The stimulatory effect of TMPS was abolished by siRNA-mediated P2Y6 knockdown and diisothiocyanate derivative MRS 2578, a selective antagonist of the P2Y6R. Our results indicate for the first time that increased stability of thymidine 5'-O-monophosphorothioate as well as its affinity toward the P2Y6R may be responsible for some long-term effects mediated by this receptor.

UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis.[Pubmed:17410128]

Nature. 2007 Apr 26;446(7139):1091-5.

Microglia, brain immune cells, engage in the clearance of dead cells or dangerous debris, which is crucial to the maintenance of brain functions. When a neighbouring cell is injured, microglia move rapidly towards it or extend a process to engulf the injured cell. Because cells release or leak ATP when they are stimulated or injured, extracellular nucleotides are thought to be involved in these events. In fact, ATP triggers a dynamic change in the motility of microglia in vitro and in vivo, a previously unrecognized mechanism underlying microglial chemotaxis; in contrast, microglial phagocytosis has received only limited attention. Here we show that microglia express the metabotropic P2Y6 receptor whose activation by endogenous agonist UDP triggers microglial phagocytosis. UDP facilitated the uptake of microspheres in a P2Y6-receptor-dependent manner, which was mimicked by the leakage of endogenous UDP when hippocampal neurons were damaged by kainic acid in vivo and in vitro. In addition, systemic administration of kainic acid in rats resulted in neuronal cell death in the hippocampal CA1 and CA3 regions, where increases in messenger RNA encoding P2Y6 receptors that colocalized with activated microglia were observed. Thus, the P2Y6 receptor is upregulated when neurons are damaged, and could function as a sensor for phagocytosis by sensing diffusible UDP signals, which is a previously unknown pathophysiological function of P2 receptors in microglia.

Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo.[Pubmed:17322022]

J Leukoc Biol. 2007 May;81(5):1269-75.

Extracellular nucleotides are emerging as important inflammatory mediators. Here, we demonstrate that these molecules mediate LPS-induced neutrophil migration in vitro and in vivo. Apyrase, a nucleotide scavenger, reduced the ability of LPS-stimulated monocytes to recruit neutrophils, as assayed using a modified Boyden chamber. This effect resulted from the inhibition of IL-8 release from monocytes. Furthermore, LPS-induced IL-8 release by monocytes was attenuated significantly by P2Y6 receptor antagonists, RB-2 and MRS2578. Reciprocally, UDP, the selective P2Y6 agonist, induced IL-8 release by monocytes. As for LPS, the media of UDP-stimulated monocytes were chemotactic for neutrophils; IL-8 accounted for approximately 50% of neutrophil migration induced by the media of LPS- or UDP-treated monocytes in transendothelial migration assays. It is important that in the murine air-pouch model, extracellular nucleotides were instrumental in LPS-induced neutrophil migration. Altogether, these data imply that LPS induces the release of nucleotides from monocytes and that by autocrine stimulation, the latter molecules regulate neutrophil migration caused by Gram-negative bacteria, suggesting a proinflammatory role of extracellular nucleotides in innate immunity.

Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors.[Pubmed:15081875]

Biochem Pharmacol. 2004 May 1;67(9):1763-70.

The physiological role of the P2Y(6) nucleotide receptor may involve cardiovascular, immune and digestive functions based on the receptor tissue distribution, and selective antagonists for this receptor are lacking. We have synthesized a series of symmetric aryl diisothiocyanate derivatives and examined their ability to inhibit phospholipase C (PLC) activity induced by activation of five subtypes of recombinant P2Y receptors. Several derivatives were more potent at inhibiting action of UDP at both human and rat P2Y(6) receptors expressed in 1321N1 human astrocytes than activation of human P2Y(1), P2Y(2), P2Y(4) and P2Y(11) receptors. The inhibition by diisothiocyanate derivatives of 1,2-diphenylethane (MRS2567) and 1,4-di-(phenylthioureido) butane (MRS2578) was concentration-dependent and insurmountable, with IC(50) values of 126+/-15 nM and 37+/-16 nM (human) and 101+/-27 nM and 98+/-11 nM (rat), respectively. A derivative of 1,4-phenylendiisothiocyanate (MRS2575) inhibited only human but not rat P2Y(6) receptor activity. MRS2567 and MRS2578 at 10microM did not affect the UTP (100nM)-induced responses of cells expressing P2Y(2) and P2Y(4) receptors, nor did they affect the 2-methylthio-ADP (30nM)-induced responses at the P2Y(1) receptor or the ATP (10microM)-induced responses at the P2Y(11) receptor. Other antagonists displayed mixed selectivities. The selective antagonists MRS2567, MRS2575 and MRS2578 (1microM) completely blocked the protection by UDP of cells undergoing TNFalpha-induced apoptosis. Thus, we have identified potent, insurmountable antagonists of P2Y(6) receptors that are selective within the family of PLC-coupled P2Y receptors.

MRS 2578 is a selective and potent P2Y6 receptor antagonist with IC50s of 37 nM (human) and 98 nM (rat). MRS 2578 exhibits insignificant activity at P2Y1, P2Y2, P2Y4, and P2Y11 receptors.

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