Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Ko, Hyojin; Carter, Rhonda L.; Cosyn, Liesbet; Petrelli, Riccardo; Castro, Sonia de; Besada, Pedro; Zhou, Yixing; Cappellacci, Loredana; Franchetti, Palmarisa; Grifantini, Mario; Calenbergh, Serge Van; Harden, T. Kendall; Jacobson, Kenneth A.

doi:10.1016/j.bmc.2008.05.013

Cited by 66 publications

(98 citation statements)

References 35 publications

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“…In the absence of the P2Y 2 receptor, the protective effect of UTP was abolished. Uridine-5′-tetraphosphate δ-phenyl ester (MRS2768) is a selective and moderately potent P2Y 2 receptor agonist with enhanced stability against the action of ectonucleotidases [20]. In the present work, we provide evidence that the P2Y 2 receptor agonist MRS2768 has cardioprotective effects both in vitro and in vivo.…”

Section: Introductionsupporting

confidence: 48%

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Hochhauser

Cohen

Waldman

et al. 2013

Purinergic Signalling

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Extracellular nucleotides acting via P2 receptors play important roles in cardiovascular physiology/pathophysiology. Pyrimidine nucleotides activate four G protein-coupled P2Y receptors (P2YRs): P2Y 2 and P2Y 4 (UTP-activated), P2Y 6 , and P2Y 14 . Previously, we showed that uridine 5′-triphosphate (UTP) activating P2Y 2 R reduced infarct size and improved mouse heart function after myocardial infarct (MI). Here, we examined the cardioprotective role of P2Y 2 R in vitro and in vivo following MI using uridine-5′-tetraphosphate δ-phenyl ester tetrasodium salt (MRS2768), a selective and more stable P2Y 2 R agonist. Cultured rat cardiomyocytes pretreated with MRS2768 displayed protection from hypoxia [as revealed by lactate dehydrogenase (LDH) release and propidium iodide (PI) binding], which was reduced by P2Y 2 R antagonist, AR-C118925 (5-((5-(2,8-dimethyl-5H-dibenzo [a,d][7]annulen-5-yl)-2-oxo-4-thioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-N-(1H-tetrazol-5-yl)furan-2-carboxamide). In vivo, echocardiography and infarct size staining of triphenyltetrazolium chloride (TTC) in 3 groups of mice 24 h post-MI: sham, MI, and MI+MRS2768 indicated protection. Fractional shortening (FS) was higher in MRS2768-treated mice than in MI alone (40.0±3.1 % vs. 33.4±2.7 %, p < 0.001). Troponin T and tumor necrosis factor-α (TNF-α) measurements demonstrated that MRS2768 pretreatment reduced myocardial damage (p<0.05) and c-Jun phosphorylation increased. Thus, P2Y 2 R activation protects cardiomyocytes from hypoxia in vitro and reduces post-ischemic myocardial damage in vivo.

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Section: Introductionsupporting

confidence: 48%

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Hochhauser

Cohen

Waldman

et al. 2013

Purinergic Signalling

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“…Nucleoside polyphosphates beyond 59-triphosphates, e.g., uridine 59-tetraphosphate, are also reported to activate various P2YR subtypes (Ko et al, 2008). Bifunctional agonist analogs of Up 4 U [P 1 -(59-uridinyl)-P 4 -(59-uridinyl)-tetraphosphate] and uridine 59-tetraphosphate glucose are tolerated at P2Y 2 , P2Y 4 , and P2Y 6 receptors.…”

Section: Medicinal Chemistry Of P2yrs: Focus On Nucleotidesmentioning

confidence: 99%

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

et al. 2015

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Eight G protein-coupled P2Y receptor (P2YR) subtypes are important physiologic mediators. The human P2YRs are fully activated by ATP (P2Y 2 and P2Y 11 ), ADP (P2Y 1 , P2Y 12 , and P2Y 13 ), UTP (P2Y 2 and P2Y 4 ), UDP (P2Y 6 and P2Y 14 ), and UDP glucose (P2Y 14 ). Their structural elucidation is progressing rapidly. The X-ray structures of three ligand complexes of the G i -coupled P2Y 12 R and two of the G q -coupled P2Y 1 Rs were recently determined and will be especially useful in structure-based ligand design at two P2YR subfamilies. These high-resolution structures, which display unusual binding site features, complement mutagenesis studies for probing ligand recognition and activation. The structural requirements for nucleotide agonist recognition at P2YRs are relatively permissive with respect to the length of the phosphate moiety, but less so with respect to base recognition. Nucleotide-like antagonists and partial agonists are also known for P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 12 Rs. Each P2YR subtype has the ability to be activated by structurally bifunctional agonists, such as dinucleotides, typically, dinucleoside triphosphates or tetraphosphates, and nucleoside polyphosphate sugars (e.g., UDP glucose) as well as the more conventional mononucleotide agonists. A range of dinucleoside polyphosphates, from triphosphates to higher homologs, occurs naturally. Earlier modeling predictions of the P2YRs were not very accurate, but recent findings have provided much detailed structural insight into this receptor family to aid in the rational design of new drugs.

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“…However, we believe that UTP acted at P2Y 4 receptors since the contraction to UTP was significantly inhibited by both endothelium removal and in the presence of DUP 697, but responses to ATP were unaffected. UTP-induced contraction may also be mediated by P2Y 2 receptors, since MRS2768 which is a selective agonist at P2Y 2 receptors and displays no affinity for P2Y 4 or P2Y 6 receptors was able to evoke a contraction in pancreatic arteries [32] (Fig. 1a).…”

Section: Discussionmentioning

confidence: 99%

Investigation of the functional expression of purine and pyrimidine receptors in porcine isolated pancreatic arteries

Alsaqati

Chan

Ralevic

2013

Purinergic Signalling

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Receptors for purines and pyrimidines are expressed throughout the cardiovascular system. This study investigated their functional expression in porcine isolated pancreatic arteries. Pancreatic arteries (endothelium intact or denuded) were prepared for isometric tension recording and preconstricted with U46619, a thromboxane A 2 mimetic; adenosine-5′-diphosphate (ADP), uridine-5′-triphosphate (UTP) and MRS2768, a selective P2Y 2 agonist, were applied cumulatively, while adenosine-5′-triphosphate (ATP) and αβ-methylene-ATP (αβ-meATP) response curves were generated from single concentrations per tissue segment. Antagonists/ enzyme inhibitors were applied prior to U46619 addition. ATP, αβ-meATP, UTP and MRS2768 induced vasoconstriction, with a potency order of αβ-meATP > MRS2768 > ATP ≥ UTP. Contractions to ATP and αβ-meATP were blocked by NF449, a selective P2X1 receptor antagonist. The contraction induced by ATP, but not UTP, was followed by vasorelaxation. Endothelium removal and DUP 697, a cyclooxygenase-2 inhibitor, had no significant effect on contraction to ATP but attenuated that to UTP, indicating actions at distinct receptors. MRS2578, a selective P2Y 6 receptor antagonist, had no effect on contractions to UTP. ADP induced endothelium-dependent vasorelaxation which was inhibited by MRS2179, a selective P2Y 1 receptor antagonist, or SCH58261, a selective adenosine A 2A receptor antagonist. The contractions to ATP and αβ-meATP were attributed to actions at P2X1 receptors on the vascular smooth muscle, whereas it was shown for the first time that UTP induced an endothelium-dependent vasoconstriction which may involve P2Y 2 and/or P2Y 4 receptors. The relaxation induced by ADP is mediated by P2Y 1 and A 2A adenosine receptors. Porcine pancreatic arteries appear to lack vasorelaxant P2Y 2 and P2Y 4 receptors.

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Synthesis and potency of novel uracil nucleotides and derivatives as P2Y2 and P2Y6 receptor agonists

Cited by 66 publications

References 35 publications

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

P2Y2 receptor agonist with enhanced stability protects the heart from ischemic damage in vitro and in vivo

Nucleotides Acting at P2Y Receptors: Connecting Structure and Function

Investigation of the functional expression of purine and pyrimidine receptors in porcine isolated pancreatic arteries

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