Constitutional isomers of Reactive Blue 2 – selective P2Y-receptor antagonists?

Glänzel, Markus; Bültmann, Ralph; Starke, Klaus; Frahm, A. W.

doi:10.1016/s0223-5234(02)01449-6

Cited by 49 publications

(41 citation statements)

References 30 publications

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“…The molecular structure of RB-2 contains three sulfonic acid residues. RB-2 is defined as a mixture of two constitutional isomers with a sulfonic acid residue in the meta-and para-position at ring F, respectively (CAS number 12236-82-7; see also Glä nzel et al, 2003Glä nzel et al, , 2005. The data of our present study indicate that the sulfonic acid residue at ring D of antagonists based on the structure of RB-2 ( Fig.…”

mentioning

confidence: 57%

“…The following drugs were used: adenosine 5Ј-diphosphate sodium salt (ADP), adenosine 5Ј-triphosphate sodium salt (ATP), forskolin, 2-methylthioadenosine 5Ј-diphosphate trisodium salt (2-methylthio-ADP, 2-MeSADP), reactive red 2 and uridine 5Ј-diphosphate-glucose (UDP-glucose; Sigma Chemie, Deisenhofen, Germany); 3Ј-O-(4-benzoyl)benzoyl-ATP sodium (Invitrogen); RB-2 (mixture of reactive blue 2 meta and reactive blue 2 para; Ega Chemie, Mannheim, Germany); cibacron blue 3GA, MG 38-1 (for structure see Glä nzel et al, 2003Glä nzel et al, , 2005, reactive blue 2 meta, and reactive blue 2 para (synthesized by Markus Glä nzel, Department of Pharmacology and Toxicology, University of Freiburg; for structures see Glä nzel et al, 2003Glä nzel et al, , 2005; PSB-0739 (see Fig. 1), PSB-0801 (see Fig.…”

Section: Methodsmentioning

confidence: 99%

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Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor

Hoffmann¹,

Baqi²,

Morena³

et al. 2009

J Pharmacol Exp Ther

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The P2Y 12 receptor plays a crucial role in platelet aggregation. In the present study, we analyzed the properties of non-nucleotide antagonists at the recombinant human P2Y 12 receptor and searched for amino acids involved in the molecular interaction. Receptor function was assessed by measuring the cAMP response element (CRE)-directed luciferase expression in Chinese hamster ovary cells. The cellular cAMP production was accelerated by forskolin; 2-methylthio-ADP was used to activate the wild-type P2Y 12 receptor or mutant constructs. 2-Methylthio-ADP inhibited the CRE-dependent luciferase expression with an IC 50 value of approximately 1 nM. The anthraquinone derivative reactive blue 2 used at increasing concentrations shifted the concentration-response curve of 2-methylthio-ADP to the right in a manner compatible with competitive antagonism (pA 2 value, 7.4). Its analog, 1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-0739), showed a markedly higher antagonistic potency with a pA 2 value of 9.8. In cells expressing the R256A-mutant receptor, the potencies of both reactive blue 2 (apparent pK B , 5.9) and PSB-0739 (apparent pK B , 9.1) were decreased. The same was true for the pure reactive blue 2 meta-and para-isomers and for the ortho-isomer cibacron blue 3GA. In contrast, the analog, 1-amino-4-[4-anilino-phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, lacking a sulfonic acid residue at ring D (PSB-0826), showed similar pK B values at wild-type (8.4) and R256A-mutant receptors (8.3). In summary, the results demonstrate that PSB-0739 is the most potent competitive nonnucleotide antagonist at the human P2Y 12 receptor described so far. The results also indicate that the sulfonic acid residue at ring D is involved in the interaction of antagonists derived from reactive blue 2 with the residue Arg256 of the human P2Y 12 receptor.

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confidence: 57%

Section: Methodsmentioning

confidence: 99%

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor

Hoffmann¹,

Baqi²,

Morena³

et al. 2009

J Pharmacol Exp Ther

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“…This could have been predicted from their limited potencies [26]. It is noteworthy that the properties of RB-2 vary from batch to batch [31], and MRS2578 is not stable in aqueous solutions [26]. MRS2578 blocked IL-8 release more efficiently in UDP-stimulated monocytes than in LPS-treated cells.…”

Section: Discussionmentioning

confidence: 99%

Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo

Kukulski

Yebdri

Lefebvre

et al. 2007

Journal of Leukocyte Biology

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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 P2Y 6 receptor antagonists, RB-2 and MRS2578. Reciprocally, UDP, the selective P2Y 6 agonist, induced IL-8 release by monocytes. As for LPS, the media of UDPstimulated monocytes were chemotactic for neutrophils; IL-8 accounted for ~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.

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“…Although there is a lack of consensus about the P2Y versus P2X selectivity of reactive blue 2, it consistently does not block vasorelaxations to adenosine Rump et al, 1998;Glänzel et al, 2003). a,b-MeATP was the most potent agonist of a series of analogs producing contractions of the rabbit ear artery , suggesting that the receptor involved is the P2X 1 (or P2X 3 ) subtype.…”

Section: Ear Arterymentioning

confidence: 99%

Purinergic Signaling and Blood Vessels in Health and Disease

2013

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Constitutional isomers of Reactive Blue 2 – selective P2Y-receptor antagonists?

Cited by 49 publications

References 30 publications

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor

Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo

Purinergic Signaling and Blood Vessels in Health and Disease

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Constitutional isomers of Reactive Blue 2 – selective P2Y-receptor antagonists?

Cited by 49 publications

References 30 publications

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y12 Receptor

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y12 Receptor

Extracellular nucleotides mediate LPS-induced neutrophil migration in vitro and in vivo

Purinergic Signaling and Blood Vessels in Health and Disease

Contact Info

Product

Resources

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Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor

Interaction of New, Very Potent Non-Nucleotide Antagonists with Arg256 of the Human Platelet P2Y₁₂ Receptor