The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14

Gauthier, Jacques Yves; Belley, Michel; Deschênes, Denis; Fournier, Jean-François; Gagné, Sébastien; Gareau, Yves; Hamel, Martine; Hénault, Martin; Hyjazie, Huda; Kargman, Stacia; Lavallée, Geneviève; Lévesque, Jean-François; Li, Lianhai; Mamane, Yaël; Mancini, Joseph A.; Morin, Nicolas; Mulrooney, Erin F.; Robichaud, Jacques; Thérien, Michel; Tranmer, Geoffrey K.; Wang, Zhaoyin; Wu, Jin; Black, W. Cameron

doi:10.1016/j.bmcl.2011.03.081

Cited by 44 publications

(48 citation statements)

References 7 publications

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“…Of all the P2YR subtypes studied, it seems only the role of the P2Y 14 R in degranulation was unambiguously defined, based on the potent facilitation by the synthetic P2Y 14 R agonist MRS2690 (EC 50 229 nM, comparable to its known potency at the human P2Y 14 R [12]), the inhibition by PTX, the P2Y 14 R antagonist PPTN [32], and specific siRNA for the P2Y 14 R. Thus, human mast cells express an endogenous P2Y 14 R, which facilitates degranulation in a Fig. 4 Effects of PTX, P2Y 14 R siRNA and a novel P2Y 14 R antagonist PPTN [32] on P2Y 14 R-mediated enhancement of β-Hex release.…”

Section: Discussionmentioning

confidence: 99%

“…4 Effects of PTX, P2Y 14 R siRNA and a novel P2Y 14 R antagonist PPTN [32] on P2Y 14 R-mediated enhancement of β-Hex release. a LAD2 cells were split to 96-well plates (10 4 cells/well) and incubated overnight with 100 ng/ml anti-NP-specific IgE antibody and 100 ng/ml pertussis toxin (PTX).…”

Section: Discussionmentioning

confidence: 99%

“…Selective P2Y 14 R antagonists have been reported [32] and therefore could be examined in models of asthma. Degranulation mediated via ADP or ATP likely involves multiple purine receptors, including ARs.…”

Section: Discussionmentioning

confidence: 99%

“…C3a (catalog number 204881) was from EMD Biosciences (La Jolla, CA, USA). 4-(4-(Piperidin-4-yl)phenyl)-7-(4-(trifluoromethyl)phenyl)-2-naphthoic acid (mesylate salt form) (PPTN) was synthesized at NIDDK, National Institutes of Health as previously described [32,33]. All other reagents were from standard sources and are of analytical grade.…”

Section: Methodsmentioning

confidence: 99%

“…Figure 4a shows that pertussis toxin (PTX) treatment (100 ng/ml) did not affect NP-induced β-Hex release but significantly blunted the enhancement of β-Hex release induced by MRS2690 (1 μM), consistent with a role of the G i -coupled P2Y 14 R. Figure 4b shows that the P2Y 14 R siRNA significantly diminished MRS2690-caused enhancement of C3a-induced β-Hex release. Figure 4c shows that a novel, potent P2Y 14 R antagonist, PPTN [32], significantly inhibited MRS2690-induced enhancement of C3a-induced β-Hex release. PPTN did not significantly affect the effect of C3a (P > 0.05).…”

Section: Effects Of Various Nucleotides On Antigen and C3a-mediated Dmentioning

confidence: 98%

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The role of P2Y14 and other P2Y receptors in degranulation of human LAD2 mast cells

Gao

Wei

Jayasekara

et al. 2012

Purinergic Signalling

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Mast cell degranulation affects many conditions, e.g., asthma and urticaria. We explored the potential role of the P2Y 14 receptor (P2Y 14 R) and other P2Y subtypes in degranulation of human LAD2 mast cells. All eight P2YRs were expressed at variable levels in LAD2 cells (quantitative real-time RT-PCR). Gene expression levels of ADP receptors, P2Y 1 R, P2Y 12 R, and P2Y 13 R, were similar, and P2Y 11 R and P2Y 4 R were highly expressed at 5.8-and 3.8-fold of P2Y 1 R, respectively. Least expressed P2Y 2 R was 40-fold lower than P2Y 1 R, and P2Y 6 R and P2Y 14 R were ≤50 % of P2Y 1 R. None of the native P2YR agonists alone induced β-hexosaminidase (β-Hex) release, but some nucleotides significantly enhanced β-Hex release induced by C3a or antigen, with a rank efficacy order of ATP>UDPG≥ADP>>UDP, UTP. Although P2Y 11 R and P2Y 4 R are highly expressed, they did not seem to play a major role in degranulation as neither P2Y 4 R agonist UTP nor P2Y 11 R agonists ATPγS and NF546 had a substantial effect. P2Y 1 Rselective agonist MRS2365 enhanced degranulation, but 1,000-fold weaker compared to its P2Y 1 R potency, and the effect of P2Y 6 R agonist 3-phenacyl-UDP was negligible. The enhancement by ADP and ATP appears mediated via multiple receptors. Both UDPG and a synthetic agonist of the P2Y 14 R, MRS2690, enhanced C3a-induced β-Hex release, which was inhibited by a P2Y 14 R antagonist, specific P2Y 14 R siRNA and pertussis toxin, suggesting a role of P2Y 14 R activation in promoting human mast cell degranulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Effects Of Various Nucleotides On Antigen and C3a-mediated Dmentioning

confidence: 98%

See 3 more Smart Citations

The role of P2Y14 and other P2Y receptors in degranulation of human LAD2 mast cells

Gao

Wei

Jayasekara

et al. 2012

Purinergic Signalling

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Diastereoselective Transfer of Tri(di)fluoroacetylsilanes‐Derived Carbenes to Alkenes

et al. 2022

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Stereoselective cyclopropanation reaction of alkenes is usually achieved by metal complexes via singlet‐metal‐carbene intermediates. However, previous transition‐metal‐catalyzed cyclopropanation of alkenes with acylsilanes afforded low diastereoselectivity. Herein, we report the first visible‐light‐induced transition‐metal‐free cyclopropanation reaction of terminal alkenes with trifluoroacetylsilanes and difluoroacetylsilanes. Both aromatic and aliphatic alkenes as well as electron‐deficient alkenes are suitable substrates for the highly cis‐selective [2+1] cyclization reaction. A combination of experimental and computational studies identified triplet carbenes as being key intermediates in this transformation. The gram scale reaction and late‐stage functionalization demonstrated the synthetic potential of this strategy.

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Diastereoselective Transfer of Tri(di)fluoroacetylsilanes‐Derived Carbenes to Alkenes

et al. 2022

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Stereoselective cyclopropanation reaction of alkenes is usually achieved by metal complexes via singlet-metal-carbene intermediates. However, previous transition-metal-catalyzed cyclopropanation of alkenes with acylsilanes afforded low diastereoselectivity. Herein, we report the first visible-light-induced transitionmetal-free cyclopropanation reaction of terminal alkenes with trifluoroacetylsilanes and difluoroacetylsilanes. Both aromatic and aliphatic alkenes as well as electron-deficient alkenes are suitable substrates for the highly cis-selective [2+1] cyclization reaction. A combination of experimental and computational studies identified triplet carbenes as being key intermediates in this transformation. The gram scale reaction and late-stage functionalization demonstrated the synthetic potential of this strategy.

show abstract

The identification of 4,7-disubstituted naphthoic acid derivatives as UDP-competitive antagonists of P2Y14

Cited by 44 publications

References 7 publications

The role of P2Y14 and other P2Y receptors in degranulation of human LAD2 mast cells

The role of P2Y14 and other P2Y receptors in degranulation of human LAD2 mast cells

Diastereoselective Transfer of Tri(di)fluoroacetylsilanes‐Derived Carbenes to Alkenes

Diastereoselective Transfer of Tri(di)fluoroacetylsilanes‐Derived Carbenes to Alkenes

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