Nandanan E, Jang S Y, Moro S, Kim H O, Siddiqui M A, Russ P, Marquez V E, Busson R, Herdewijn P, Harden T K, Boyer J L, Jacobson K A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
J Med Chem. 2000 Mar 9;43(5):829-42. doi: 10.1021/jm990249v.
The structure-activity relationships of adenosine-3', 5'-bisphosphates as P2Y(1) receptor antagonists have been explored, revealing the potency-enhancing effects of the N(6)-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-NH(2) (N)-analogue was a pure agonist of EC(50) 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 IC(50) 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 IC(50) of 805 nM, while morpholine ring-containing analogues were nearly inactive. Anhydrohexitol ring-modified bisphosphate derivatives displayed micromolar potency as agonists (6-NH(2)) 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.
已对作为P2Y(1)受体拮抗剂的腺苷3',5'-二磷酸的构效关系进行了研究，揭示了N(6)-甲基的增效作用以及取代核糖部分的能力（Nandanan等人，《药物化学杂志》，1999年，42卷，1625 - 1638页）。我们引入了受限碳环（以探究糖折叠的作用）、与腺嘌呤部分的非糖苷键以及磷酸基团移位。通过测量每种类似物在火鸡红细胞膜中刺激磷脂酶C的能力（激动剂效应）以及抑制由30 nM 2-甲硫基腺苷-5'-二磷酸引发的刺激的能力（拮抗剂效应），对其在P2Y(1)受体上的生物活性进行了表征。在几种情况下添加N(6)-甲基可将纯激动剂转变为拮抗剂。一种碳环N(6)-甲基-2'-脱氧腺苷二磷酸类似物是一种纯P2Y(1)受体拮抗剂，且与核糖类似物（MRS 2179）等效。在一系列环受限的甲碳环衍生物中，稠合环丙烷部分将核苷的假糖环限制为在假旋转循环中定义的北（N）或南（S）构象，6-NH(2)（N）-类似物是一种EC(50)为155 nM的纯激动剂，比相应的（S）-异构体强86倍。2-氯-N(6)-甲基-（N）-甲碳环类似物是一种IC(50)为51.6 nM的拮抗剂。因此，核糖环（N）-构象在P2Y(1)受体识别中似乎更受青睐。一种环丁基类似物是一种IC(50)为805 nM的拮抗剂，而含吗啉环的类似物几乎无活性。脱水己糖醇环修饰的二磷酸衍生物作为激动剂（6-NH(2)）或拮抗剂（N(6)-甲基）表现出微摩尔级别的效力。强效拮抗剂能量最小化结构的分子模型表明，两个磷酸基团可能占据共同区域。（N）-和（S）-甲碳环激动剂类似物被对接至先前报道的P2Y(1)受体模型的假定结合位点。
