Synthesis, biological activity, and molecular modeling of ribose-modified deoxyadenosine bisphosphate analogues as P2Y1 receptor ligands
Synthesis, biological activity, and molecular modeling of ribose-modified deoxyadenosine bisphosphate analogues as P2Y1 receptor ligands
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DOI：
10.1021/jm990249v
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发表时间：
2000-03-09
影响因子：
7.3
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Nandanan, E;Jang, SY;Jacobson, KA
已经探索了作为P2Y(1)受体拮抗剂的腺苷-3‘，5’-二磷酸的构效关系，揭示了NG-甲基的效力增强作用和取代核糖部分的能力(Nandanan等人)。J.Med.化学。1999、42、1625-1638)。我们引入了限制碳环环(以探索糖折叠的作用)，腺嘌呤部分的非糖基键，以及磷酸基团的移动。通过测定其刺激火鸡红细胞膜上磷脂酶C的能力(激动剂效应)和抑制30 nM 2-甲基硫代腺苷-5‘-二磷酸(拮抗剂效应)对其刺激的能力来表征其在P2Y(1)受体上的生物活性。在几种情况下，N-6-甲基的加入将纯激动剂转化为拮抗剂。碳环N-6-甲基-2‘-脱氧腺苷二磷酸类似物是一种纯的P2Y(1)受体拮抗剂，与核糖类似物(MRS 2179)等效性。在一系列环约束甲胺卡巴衍生物中，稠合的环丙烷部分将核苷的假糖环限制在假旋转循环中定义的Northern(N)或Southern(S)构象中，6-NH_2(N)类似物是EC50 155 nm的纯激动剂，比相应的(S)-异构体的效力高86倍。2-氯-N-6-甲基-(N)-甲基卡巴类似物是IC50 51.6 nM的拮抗剂。因此，核糖环(N)-构象似乎更有利于在P2Y(1)受体上识别。环丁基类似物是一种拮抗剂，其IC50为805 nM，而含有吗啉环的类似物几乎没有活性。脱水己醇环修饰的二磷酸衍生物表现出作为激动剂(6-NH_2)或拮抗剂(N-6-甲基)的微摩尔效力。一个强有力的拮抗剂的能量最小化结构的分子模型表明，这两个磷酸基团可能占据共同的区域。(N)-和(S)-甲烷胺激动剂类似物被对接到先前报道的P2Y(1)受体模型的假定结合部位。
The structure-activity relationships of adenosine-3',5'-bisphosphates as P2Y(1) receptor antagonists have been explored, revealing the potency-enhancing effects of the NG-methyl group and the ability to substitute the ribose moiety (Nandanan et al. J. Med. Chem. 1999, 42, 1625-1638). We have introduced constrained carbocyclic rings (to explore the role of sugar puckering), non-glycosyl bonds to the adenine moiety, and a phosphate group shift. The biological activity of each analogue at P2Y(1) receptors was characterized by measuring its capacity to stimulate phospholipase C in turkey erythrocyte membranes (agonist effect) and to inhibit its stimulation elicited by 30 nM 2-methylthioadenosine-5'-diphosphate (antagonist effect). Addition of the N-6-methyl group in several cases converted pure agonists to antagonists. A carbocyclic N-6-methyl-2'-deoxyadenosine bisphosphate analogue was a pure P2Y(1) receptor antagonist and equipotent to the ribose analogue (MRS 2179). In the series of ring-constrained methanocarba derivatives where a fused cyclopropane moiety constrained the pseudosugar ring of the nucleoside to either a Northern (N) or Southern (S) conformation, as defined in the pseudorotational cycle, the 6-NH2 (N)-analogue was a pure agonist of EC50 155 nM and 86-fold more potent than the corresponding (S)-isomer. The 2-chloro-N-6-methyl-(N)-methanocarba analogue was an antagonist of IC50 51.6 nM. Thus, the ribose ring (N)-conformation appeared to be favored in recognition at P2Y(1) receptors. A cyclobutyl analogue was an antagonist with IC50 of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives displayed micromolar potency as agonists (6-NH2) or antagonists (N-6-methyl). A molecular model of the energy-minimized structures of the potent antagonists suggested that the two phosphate groups may occupy common regions. The (N)- and (S)-methanocarba agonist analogues were docked into the putative binding site of the previously reported P2Y(1) receptor model.