- High-affinity, non-nucleotide-derived competitive antagonists of platelet P2Y12 receptors
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Anthraquinone derivatives related to the moderately potent, nonselective P2Y12 receptor antagonist reactive blue 2 (6) have been synthesized and optimized with respect to P2Y12 receptor affinity. A radioligand binding assay utilizing human blood platelet membranes and the P2Y12 receptor-selective antagonist radioligand [3H]2-propylthioadenosine- 5′-adenylic acid (1,1-dichloro-1-phosphonomethyl-1-phosphonyl) anhydride ([3H]PSB-0413) was applied for compound testing. 1-Amino-2- sulfoanthraquinone derivatives bearing a (p-phenylamino) anilino substitution in the 4-position and an additional acidic function in the meta-position of the aniline ring showed high P2Y12 receptor affinity. These new anthraquinone derivatives became accessible by a recently developed copper(0)-catalyzed Ullmann coupling reaction of 1-amino-4-bromoanthraquinone derivatives with anilines in phosphate buffer under microwave irradiation. The most potent compounds exhibited Ki values of 24.9 nM (1-amino-4-[4-phenylamino-3-sulfophenylamino]-9,10-dioxo-9,10-dihydroanthracene- 2-sulfonate, PSB-0739, 39), and 21.0 nM (1-amino-4-[4-phenylamino-3- carboxyphenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate, PSB-0702, 41), respectively. 1-Amino-2-sulfo-4-anilinoanthraquinone derivatives appeared to be noncytotoxic, as shown for selected derivatives at two human cell lines (melanoma and astrocytoma). Compounds 39 and 41 represent new lead structures for the development of antithrombotic drugs.
- Baqi, Younis,Atzler, Kerstin,K?se, Meryem,Gl?nzel, Markus,Müller, Christa E.
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supporting information; experimental part
p. 3784 - 3793
(2010/04/24)
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- Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2
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P2 membrane receptors for nucleotides represent significant targets for experimental pharmacology and drug research. In earlier publications, we have shown that Reactive Blue 2 (RB 2), one of the most widely used P2-receptor antagonists, displays only moderate affinity and does not discriminate between native P2X- and P2Y-receptor subtypes. In the present study we have pharmacologically evaluated a series of 15 synthesized and re-evaluated four commercially obtained and chromatographically purified RB 2 type anthraquinone derivatives on contractions of the rat vas deferens (RVD) elicited by α,β-methylene ATP (α,β-meATP), mediated by P2X 1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5′-O-(2- thiodiphosphate) (ADPβS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic π-electron systems, hydrogen bonds with nitrogen as donor and acceptor atoms, and, particularly, position, conformational distance and number of anionic sulfonate groups are of great importance for the blockade of the two native P2-receptor subtypes. We have also identified novel, for the most part reversible antagonists that bind with higher affinity and improved subtype selectivity in comparison to RB 2. In particular, 1-amino-4-{4-[4- chloro-6-(2-sulfonatophenylamino)-[1,3,5]triazine-2-ylamino]-2- sulfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y 1-like-receptors of the GPTC reported so far (IC50 = 4.6:nM). It is significantly less potent as reversible antagonist at the P2X1-receptors of the RVD (IC50 = 2.8 μM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations.
- Gl?nzel, Markus,Bültmann, Ralph,Starke, Klaus,Frahm, August W.
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p. 1262 - 1276
(2007/10/03)
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