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首页> 外文期刊>Journal of Medicinal Chemistry >Structure-activity relationships of bisphosphate nucleotide derivatives as P2Y1 receptor antagonists and partial agonists.
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Structure-activity relationships of bisphosphate nucleotide derivatives as P2Y1 receptor antagonists and partial agonists.

机译：二磷酸核苷酸衍生物作为P2Y1受体拮抗剂和部分激动剂的构效关系。

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The P2Y1 receptor is present in the heart, in skeletal and various smooth muscles, and in platelets, where its activation is linked to aggregation. Adenosine 3',5'- and 2',5'-bisphosphates have been identified as selective antagonists at the P2Y1 receptor (Boyer et al. Mol. Pharmacol. 1996, 50, 1323-1329) and have been modified structurally to increase receptor affinity (Camaioni et al. J. Med. Chem. 1998, 41, 183-190). We have extended the structure-activity relationships to a new series of deoxyadenosine bisphosphates with substitutions in the adenine base, ribose moiety, and phosphate groups. The activity of each analogue at P2Y1 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-(methylthio)adenosine 5'-diphosphate (antagonist effect). 2'-Deoxyadenosine bisphosphate analogues containing halo, amino, and thioether groups at the 2-position of the adenine ring were more potent P2Y1 receptor antagonists than analogues containing various heteroatom substitutions at the 8-position. An N6-methyl-2-chloro analogue, 6, was a full antagonist and displayed an IC50 of 206 nM. Similarly, N6-methyl-2-alkylthio derivatives 10, 14, and 15 were nearly full antagonists of IC50 < 0.5 microM. On the ribose moiety, 2'-hydroxy, 4'-thio, carbocyclic, and six-membered anhydrohexitol ring modifications have been prepared and resulted in enhanced agonist properties. The 1,5-anhydrohexitol analogue 36 was a pure agonist with an EC50 of 3 microM, i.e., similar in potency to ATP. 5'-Phosphate groups have been modified in the form of triphosphate, methyl phosphate, and cyclic 3',5'-diphosphate derivatives. The carbocyclic analogue had enhanced agonist efficacy, and the 5'-O-phosphonylmethyl modification was tolerated, suggesting that deviations from the nucleotide structure may result in improved utility as pharmacological probes. The N6-methoxy modification eliminated receptor affinity. Pyrimidine nucleoside 3', 5'-bisphosphate derivatives were inactive as agonists or antagonists at P2Y receptor subtypes.
机译：P2Y1受体存在于心脏，骨骼肌和各种平滑肌以及血小板中，其活化与聚集有关。腺苷3'，5'-和2'，5'-二磷酸酯已被鉴定为P2Y1受体的选择性拮抗剂（Boyer等人，Mol。Pharmacol。1996，50，1323-1329），并已进行结构修饰以增加受体亲和力（Camaioni等人，J。Med。Chem。1998，41，183-190）。我们已经将结构-活性关系扩展到了一系列新的脱氧腺苷二磷酸双腺嘌呤碱基，核糖部分和磷酸基团的取代。通过测量其刺激火鸡红细胞膜上的磷脂酶C（激动剂作用）和抑制10 nM 2-（甲硫基）腺苷5'-二磷酸酯引起的磷脂酶C刺激作用（拮抗剂作用）的能力，确定每种类似物对P2Y1受体的活性。 。在腺嘌呤环的2位上含有卤素，氨基和硫醚基的2'-脱氧腺苷二磷酸酯类似物比在8位上含有各种杂原子取代的类似物是更有效的P2Y1受体拮抗剂。 N6-甲基-2-氯类似物6是完全的拮抗剂，IC50为206 nM。同样，N6-甲基-2-烷硫基衍生物10、14和15几乎是IC50 <0.5 microM的完全拮抗剂。在核糖部分上，已制备了2'-羟基，4'-硫代，碳环和六元脱水己糖醇环修饰，并增强了激动剂的性能。 1，5-脱水己糖醇类似物36是纯的激动剂，EC 50为3μM，即效力类似于ATP。 5'-磷酸酯基团已被修饰为三磷酸酯，磷酸甲酯和环状3'，5'-二磷酸酯衍生物。碳环类似物具有增强的激动剂功效，并且可以耐受5'-O-膦酰基甲基修饰，这表明与核苷酸结构的偏离可能会提高药理探针的实用性。 N6-甲氧基修饰消除了受体亲和力。嘧啶核苷3'，5'-二磷酸酯衍生物作为P2Y受体亚型的激动剂或拮抗剂无效。

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