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 alpha,beta-methylene ATP (alpha,beta-meATP), mediated by P2X1-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADPbetaS), mediated by P2Y1-like receptors. Based on the structure-activity relationships (SAR) it is concluded that hydrophobic interactions of aromatic pi-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-su lfonatophenylamino}-9,10-dioxo-9,10-dihydroanthracene-2-sulfonic acid trisodium salt (MG 50-3-1) is the most potent antagonist at the P2Y1-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 microM). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations.

中文翻译：

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结构上与活性蓝2相关的新型P2受体拮抗剂的构效关系。

核苷酸的P2膜受体代表了实验药理学和药物研究的重要目标。在较早的出版物中，我们显示了反应最广泛的P2受体拮抗剂之一，反应性蓝2（RB 2）仅显示中等亲和力，不能区分天然P2X和P2Y受体亚型。在本研究中，我们已经通过药理学评估了一系列15种合成并重新评估的4种商业获得和色谱纯化的RB 2型蒽醌衍生物对α，β-亚甲基ATP（α，β）引起的大鼠输精管（RVD）收缩的影响。 -meATP）介导，并由腺苷5'-O-（2-硫代二磷酸）（ADPbetaS）诱发的，由P2Y1样受体介导的卡巴胆碱收缩的豚鼠带状大肠杆菌（GPTC）松弛。根据结构-活性关系（SAR）得出的结论是，芳香族π电子系统的疏水相互作用，与氮作为供体和受体原子的氢键，特别是阴离子磺酸盐基团的位置，构象距离和数量都很大。对于两种天然P2受体亚型的阻断具有重要意义。我们还发现了与RB 2相比具有更高亲和力和更高亚型选择性的新型可逆拮抗剂。特别是1-amino-4- {4- [4-chloro-6-（2-sulfonatophenylamino） ）-[[1,3,5]三嗪-2-基氨基] -2-磺酰基苯基氨基} -9,10-二氧代-9,10-二氢蒽-2-磺酸三钠盐（MG 50-3-1）是迄今为止，GPTC的P2Y1样受体中最有效的拮抗剂报道（IC50 = 4.6 nM）。在RVD的P2X1受体上，它作为可逆性拮抗剂的效力显着降低（IC50 = 2.8 microM）。因此，MG 50-3-1代表一种选择性的药理学工具，可能是未来研究的先导化合物。