Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2
Structure-activity relationships of novel P2-receptor antagonists structurally related to Reactive Blue 2
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DOI：
10.1016/j.ejmech.2005.07.007
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发表时间：
2005-12-01
影响因子：
6.7
通讯作者：
Frahm, AW
中科院分区：
文献类型：
--
作者：
Glänzel, M;Bültmann, R;Frahm, AW
核苷酸的P2膜受体是实验药理学和药物研究的重要靶点。在早期的出版物中，我们已经表明，活性蓝2（RB 2），最广泛使用的P2受体拮抗剂之一，显示只有中等的亲和力，并不区分天然P2 X和P2 Y受体亚型。本文对一系列15个合成的RB 2型蒽醌衍生物进行了初步评价，并对4个商业化的和色谱纯化的RB 2型蒽醌衍生物进行了再评价（α，β-meATP），由P2 X（1）-受体介导，和由P2 Y（1）样受体介导的腺苷5 '-O-（2-硫代二磷酸）（ADP β S）引起的卡巴胆碱预收缩的豚鼠结肠带（GPTC）的舒张。基于构效关系（SAR）的结论是，芳香族π电子系统的疏水相互作用，氢键与氮作为供体和受体原子，特别是，位置，构象距离和阴离子磺酸基团的数量是非常重要的两个天然P2受体亚型的封锁。我们还确定了新的，在大多数情况下可逆的拮抗剂，结合更高的亲和力和改善亚型选择性相比，RB 2。具体而言，1-氨基-4-{4-[4-氯-6-（2-磺酸基苯基氨基）-[1，3，5]三嗪-2-基氨基]-2-磺酸基苯基氨基}-9，10-二氧代-9，10-二氢蒽-2-磺酸三钠盐（MG 50-3-1）是迄今报道的GPTC的P2 Y（1）样受体的最有效拮抗剂（IC 50 = 4.6 nM）。作为RVD的P2 X（1）-受体的可逆拮抗剂，其效力明显较低（IC 50 = 2.8 μ M）。因此，MG 50-3-1代表了一种选择性的药理学工具，可能是未来研究的先导化合物。(c)2005年，Elsevier SAS。All rights reserved.
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 a,p-methylene ATP (alpha,beta-meATP), mediated by P2X(1)-receptors, and relaxations of the carbachol-precontracted guinea-pig taenia coli (GPTC) elicited by adenosine 5'-O-(2-thiodiphosphate) (ADP beta S), mediated by P2Y(1)-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-sulfonatophenylarnino}-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 P2X(1)-receptors of the RVD (IC50 = 2.8 mu M). Thus, MG 50-3-1 represents a selective pharmacological tool and may be a lead compound for future investigations. (c) 2005 Elsevier SAS. All rights reserved.