Deoxyadenosine bisphosphate derivatives as potent antagonists at P2Y1 receptors
Deoxyadenosine bisphosphate derivatives as potent antagonists at P2Y1 receptors
复制标题
DOI：
10.1021/jm970433l
复制
发表时间：
1998-01-15
影响因子：
7.3
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Camaioni, E;Boyer, JL;Jacobson, KA
腺苷3 '，5'-和2 '，5'-二磷酸先前被证明作为P2 Y（1）受体的竞争性拮抗剂（Boyer等人，Mol. Pharmacol. 1996，50，1323-1329）。在腺嘌呤环的2-和B-位、核糖部分和磷酸基团上含有各种结构修饰的2 '-和3'-脱氧腺苷二磷酸类似物已经被合成，目的是开发更有效和选择性的P2 Y（1）拮抗剂。进行腺苷核苷前体的单步磷酸化反应。通过测量其刺激火鸡红细胞膜中的磷脂酶C（激动剂效应）和抑制由10 nM 2-MeSATP引起的磷脂酶C刺激（拮抗剂效应）的能力，测定每种类似物对P2 Y（1）受体的活性。2 ′-和3 ′-脱氧修饰均耐受良好。N-6-甲基修饰将2 '-脱氧腺苷3'，5 '-二磷酸的拮抗效力（IC 50 330 nM）提高了17倍，并消除了先导化合物观察到的残余激动剂性质。N-6-乙基修饰提供了作为拮抗剂的中等效力，而N-6-丙基完全消除了激动剂和拮抗剂性质。2-甲硫基和2-氯类似物是中等效力的部分激动剂。2 '-甲氧基作为拮抗剂提供中等效力，同时增强激动剂活性。N-1-甲基类似物为弱拮抗剂，无激动剂活性。8-溴取代和N-6-氨基被甲硫基、氯或羟基取代大大降低了与P2 Y（1）受体相互作用的能力。N-6-氨基的苯甲酰化或二甲基化也消除或大大降低了拮抗剂活性。总之，我们的研究结果进一步确定了腺苷二磷酸作为P2 Y（1）受体拮抗剂的结构-活性，并导致鉴定出迄今为止报道的该受体最有效的拮抗剂。
Adenosine 3',5'- and 2',5'-bisphosphates previously were demonstrated to act as competitive antagonists at the P2Y(1) receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323-1329). 2'- and 3'-Deoxyadenosine bisphosphate analogues containing various structural modifications at the 2- and B-positions of the adenine ring, on the ribose moiety, and on the phosphate groups have been synthesized with the goal of developing more potent and selective P2Y(1) antagonists. Single-step phosphorylation reactions of adenosine nucleoside precursors were carried out. The activity of each analogue at P2Y(1) receptors was determined by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit phospholipase C stimulation elicited by 10 nM 2-MeSATP (antagonist effect). Both 2'- and 3'-deoxy modifications were well tolerated. The N-6-methyl modification both enhanced antagonistic potency (IC50 330 nM) of 2'-deoxyadenosine 3',5'-bisphosphate by 17-fold and eliminated residual agonist properties observed with the lead compounds. The N-6-ethyl modification provided intermediate potency as an antagonist, while the N-6-propyl group completely abolished both agonist and antagonist properties. 2-Methylthio and 2-chloro analogues were partial agonists of intermediate potency. A 2'-methoxy group provided intermediate potency as an antagonist while enhancing agonist activity. An N-1-methyl analogue was a weak antagonist with no agonist activity. An 8-bromo substitution and replacement of the N-6-amino group with methylthio, chloro, or hydroxy groups greatly reduced the ability to interact with P2Y(1) receptors. Benzoylation or dimethylation of the N-6-amino group also abolished or greatly diminished the antagonist activity. In summary, our results further define the structure-activity of adenosine bisphosphates as P2Y(1) receptor antagonists and have led to the identification of the most potent antagonist reported to date for this receptor.