Structure−Activity Relationships of Uridine 5‘-Diphosphate Analogues at the Human P2Y<sub>6</sub> Receptor

Besada, Pedro; Shin, Dae Hong; Costanzi, Stefano; Ko, Hyojin; Mathé, Christophe; Gagneron, Julien; Gosselin, Gilles; Maddileti, Savitri; Harden, T. Kendall; Jacobson, Kenneth A.

doi:10.1021/jm060485n

Cited by 67 publications

(83 citation statements)

References 42 publications

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“…Potential agonist activities of the UDP analogs, UDP␤S (Malmsjö et al, 2000) and 2-thio-UDP (Besada et al, 2006) also were examined in P2Y 14 -HEK293 cells. As is illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor

Carter¹,

Fricks²,

Barrett³

et al. 2009

Mol Pharmacol

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106

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The P2Y 14 receptor was initially identified as a G protein-coupled receptor activated by UDP-glucose and other nucleotide sugars. We have developed several cell lines that stably express the human P2Y 14 receptor, allowing facile examination of its coupling to native G i family G proteins and their associated downstream signaling pathways (J Pharmacol Exp Ther 330: [162][163][164][165][166][167][168] 2009). In the current study, we examined P2Y 14 receptor-dependent inhibition of cyclic AMP accumulation in human embryonic kidney (HEK) 293, C6 glioma, and Chinese hamster ovary (CHO) cells stably expressing this receptor. Not only was the human P2Y 14 receptor activated by UDP-glucose, but it also was activated by UDP. The apparent efficacies of UDP and UDP-glucose were similar, and the EC 50 values (74, 33, and 29 nM) for UDP-dependent activation of the P2Y 14 receptor in HEK293, CHO, and C6 glioma cells, respectively, were similar to the EC 50 values (323, 132, and 72 nM) observed for UDP-glucose. UDP and UDP-glucose also stimulated extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in P2Y 14 receptor-expressing HEK293 cells but not in wild-type HEK293 cells. A series of analogs of UDP were potent P2Y 14 receptor agonists, but the naturally occurring nucleoside diphosphates, CDP, GDP, and ADP exhibited agonist potencies over 100-fold less than that observed with UDP. Two UDP analogs were identified that selectively activate the P2Y 14 receptor over the UDP-activated P2Y 6 receptor, and these molecules stimulated phosphorylation of ERK1/2 in differentiated human HL-60 promyeloleukemia cells, which natively express the P2Y 14 receptor but had no effect in wild-type HL-60 cells, which do not express the receptor. We conclude that UDP is an important cognate agonist of the human P2Y 14 receptor.The metabotropic P2Y receptors include a subgroup of five receptors, the P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 receptors, that primarily signal through G q -activated signaling pathways and a subgroup of three receptors, the P2Y 12 , P2Y 13 , and P2Y 14 receptors, that primarily signal by activating heterotrimeric G proteins of the G i family (Abbracchio et al., 2006;Burnstock, 2007). The human P2Y 1 , P2Y 11 , P2Y 12 , and P2Y 13 receptors are activated by adenine nucleotides. The human P2Y 4 and P2Y 6 receptors are activated by uridine nucleotides, and the P2Y 2 receptor is activated by both ATP and UTP.

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“…Potential agonist activities of the UDP analogs, UDP␤S (Malmsjö et al, 2000) and 2-thio-UDP (Besada et al, 2006) also were examined in P2Y 14 -HEK293 cells. As is illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3 H]inositol phosphate accumulation in 1321N1 human astrocytoma cells as described previously (Besada et al, 2006). MAP Kinase Activation Assays.…”

Section: Methodsmentioning

confidence: 99%

Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor

Carter¹,

Fricks²,

Barrett³

et al. 2009

Mol Pharmacol

Self Cite

106

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“…For example, Müller and coworkers and Besada et al reported that certain 5′-triphosphate derivatives potently activate the P2Y 6 receptor. 4,5 The conformational preference of the ribose moiety in binding to uridine nucleotide-activated P2Y receptors has been explored through substitution with the sterically constrained methanocarba (bicyclo[3.1.0]hexane) ring nucleotides also were prepared by the one-pot method using a sequential reaction of 49 and 50 with phosphorus oxychloride and pyrophosphoric acid tributylammonium salt, but the yields were lower.…”

Section: Introductionmentioning

confidence: 99%

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

Carter

Cosyn

et al. 2008

Bioorganic & Medicinal Chemistry

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The phosphate, uracil, and ribose moieties of uracil nucleotides were varied structurally for evaluation of agonist activity at the human P2Y 2 , P2Y 4 , and P2Y 6 receptors. The 2-thio modification, found previously to enhance P2Y 2 receptor potency, could be combined with other favorable modifications to produce novel molecules that exhibit high potencies and receptor selectivities. Phosphonomethylene bridges introduced for stability in analogues of UDP, UTP and uracil dinucleotides markedly reduced potency. Truncation of dinucleotide agonists of the P2Y 2 receptor, in the form of Up 4 -sugars, indicated that a terminal uracil ring is not essential for moderate potency at this receptor and that specific SAR patterns are observed at this distal end of the molecule. Key compounds reported in this study include: 9, α,β-methylene-UDP, a P2Y 6 receptor agonist; 30, Up 4 -phenyl ester and 34, Up 4 -[1]glucose, selective P2Y 2 receptor agonists; 43, the 2-thio analogue of INS37217 (P 1 -(uridine 5′)-P 4 -(2′-deoxycytidine 5′) tetraphosphate), a potent and selective P2Y 2 receptor agonist.

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“…In 2007, Tocris introduced the UDP-based selective P2Y 6 agonist PSB 0474 (26) [35]. The elucidation of a 5-iodo-UDP, MRS 2693 (27), provided a potent and selective agonist at the human P2Y 6 receptor, demonstrating an EC 50 value of 15 nM in vitro and no activity at other P2Y subtypes [36]. This compound contains a large phenylacyl substituent which enhances its selectivity for P2Y 6 over P2Y 2 and P2Y 4 which may also be activated by UDP derivatives.…”

Section: Adp Atp and Udp Mimeticsmentioning

confidence: 99%

Development of a comprehensive set of P2 receptor pharmacological research compounds

Felix¹,

Martin²,

Pinion³

et al. 2011

Purinergic Signalling

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Pharmacological manipulation of P2X and P2Y receptors has been critical to the elucidation of the biological roles of these receptors within a multitude of physiological and pathological processes. Initial purinergic signalling research made use of compounds based on pyridoxal phosphate, suramin and nucleotide analogues; recently developed compounds are often derivatives of these early tools. Tocris Bioscience first entered the field of purinergic signalling reagents with the commercial release of the pyridoxal phosphate derivative, iso-PPADS. During the past two decades, Tocris has assembled a collection of over 50 compounds for P2 receptor modulation, including research tools commercialised from both academic and industrial laboratories. Recently, a number of P2X subtypeselective compounds have been generated by pharmaceutical company medicinal chemistry programmes, supplementing our range of P2Y-selective compounds. Here, we detail the current, commercially available agonists and antagonists of P2X 1,2/3,3,4,7 and P2Y 1,6,11,12 receptors; considered together, they form the foundations of a comprehensive P2 receptor pharmacological 'toolkit'.

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Structure−Activity Relationships of Uridine 5‘-Diphosphate Analogues at the Human P2Y₆ Receptor

Cited by 67 publications

References 42 publications

Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor

Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor

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

Development of a comprehensive set of P2 receptor pharmacological research compounds

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Structure−Activity Relationships of Uridine 5‘-Diphosphate Analogues at the Human P2Y6 Receptor

Cited by 67 publications

References 42 publications

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor

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

Development of a comprehensive set of P2 receptor pharmacological research compounds

Contact Info

Product

Resources

About

Structure−Activity Relationships of Uridine 5‘-Diphosphate Analogues at the Human P2Y₆ Receptor

Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor

Quantification of G_i-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y₁₄ Receptor