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P1,P2-diimidazolyl derivatives of pyrophosphate and bis-phosphonates--synthesis, properties, and use in preparation of dinucleoside tetraphosphates and analogs.焦磷酸盐和双膦酸盐的 P1，P2-二咪唑基衍生物——合成、性质及其在二核苷四磷酸和类似物制备中的应用。
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Agonist and antagonist effects of diadenosine tetraphosphate, a platelet dense granule constituent, on platelet P2Y1, P2Y12 and P2X1 receptors.二磷酸腺苷四磷酸（血小板致密颗粒的组成部分）对血小板 P2Y1、P2Y12 和 P2X1 受体的激动剂和拮抗剂作用。
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Acyl derivatives of coenzyme A inhibit platelet function via antagonism at P2Y1 and P2Y12 receptors: a new finding that may influence the design of anti-thrombotic agents.辅酶A的酰基衍生物通过拮抗P2Y1和P2Y12受体来抑制血小板功能：这一新发现可能会影响抗血栓药物的设计。
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Lipophilic modifications to dinucleoside polyphosphates and nucleotides that confer antagonist properties at the platelet P2Y12 receptor.对二核苷多磷酸和核苷酸进行亲脂性修饰，使其在血小板P2Y12受体上具有拮抗剂特性。
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Interplay between P2Y(1), P2Y(12), and P2X(1) receptors in the activation of megakaryocyte cation influx currents by ADP: evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling.P2Y(1)、P2Y(12)和P2X(1)受体在ADP激活巨核细胞阳离子内流电流中的相互作用：证据表明原代巨核细胞代表血小板P2受体信号传导的一个完全功能模型。
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具有双重特异性的修饰二腺苷四磷酸对 P2Y1 和 P2Y12 是有效的 ADP 诱导血小板激活的拮抗剂。

Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation.

机构信息

Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.

出版信息

J Thromb Haemost. 2012 Dec;10(12):2573-80. doi: 10.1111/jth.12035.

DOI:10.1111/jth.12035
PMID:23083103
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5704993/
Abstract

BACKGROUND

Diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A), a natural compound stored in platelet dense granules, inhibits ADP-induced platelet aggregation. Ap(4)A inhibits the platelet ADP receptors P2Y(1) and P2Y(12), is a partial agonist of P2Y(12), and is a full agonist of the platelet ATP-gated ion channel P2X1. Modification of the Ap(4)A tetraphosphate backbone enhances inhibition of ADP-induced platelet aggregation. However, the effects of these Ap(4)A analogs on human platelet P2Y(1), P2Y(12) and P2X1 are unclear.

OBJECTIVE

To determine the agonist and antagonist activities of diadenosine tetraphosphate analogs towards P2Y(1), P2Y(12), and P2X1.

METHODS

We synthesized the following Ap(4)A analogs: P(1),P(4)-dithiotetraphosphate; P(2),P(3)-chloromethylenetetraphosphate; P(1)-thio-P(2),P(3)-chloromethylenetetraphosphate; and P(1),P(4)-dithio-P(2),P(3)-chloromethylenetetraphosphate. We then measured the effects of these analogs on: (i) ADP-induced platelet aggregation; (ii) P2Y(1)-mediated changes in cytosolic Ca(2+); (iii) P2Y(12)-mediated changes in vasodilator-stimulated phosphoprotein phosphorylation; and (iv) P2X1-mediated entry of extracellular Ca(2+).

RESULTS

Ap(4)A analogs with modifications in the phosphate backbone inhibited both P2Y(1) and P2Y(12), and showed no agonist activity towards these receptors. The dithio modification increased inhibition of P2Y(1), P2Y(12), and platelet aggregation, whereas the chloromethylene modification increased inhibition of P2Y(12) and platelet aggregation, but decreased P2Y(1) inhibition. Combining the dithio and chloromethylene modifications increased P2Y(1) and P2Y(12) inhibition. As compared with Ap(4)A, each modification decreased agonist activity towards P2X1, and the dual modification completely eliminated P2X1 agonist activity.

CONCLUSIONS

As compared with Ap(4)A, tetraphosphate backbone analogs of Ap(4)A have diminished activity towards P2X1 but inhibit both P2Y(1) and P2Y(12) and, with greater potency, inhibit ADP-induced platelet aggregation. Thus, diadenosine tetraphosphate analogs with dual receptor selectivity may have potential as antiplatelet drugs.

摘要

背景

二腺苷 5',5'''-P(1),P(4)-四磷酸盐（Ap(4)A）是一种天然存在于血小板致密颗粒中的化合物，可抑制 ADP 诱导的血小板聚集。Ap(4)A 抑制血小板 ADP 受体 P2Y(1)和 P2Y(12)，是 P2Y(12)的部分激动剂，也是血小板 ATP 门控离子通道 P2X1 的完全激动剂。Ap(4)A 四磷酸盐骨架的修饰可增强对 ADP 诱导的血小板聚集的抑制作用。然而，这些 Ap(4)A 类似物对人血小板 P2Y(1)、P2Y(12)和 P2X1 的作用尚不清楚。

目的

确定二腺苷四磷酸类似物对 P2Y(1)、P2Y(12)和 P2X1 的激动剂和拮抗剂活性。

方法

我们合成了以下 Ap(4)A 类似物：P(1),P(4)-二硫代四磷酸盐；P(2),P(3)-氯亚甲基四磷酸盐；P(1)-硫代-P(2),P(3)-氯亚甲基四磷酸盐；和 P(1),P(4)-二硫代-P(2),P(3)-氯亚甲基四磷酸盐。然后，我们测量了这些类似物对以下方面的影响：（i）ADP 诱导的血小板聚集；（ii）P2Y(1)介导的细胞内 Ca(2+)变化；（iii）P2Y(12)介导的血管扩张刺激磷酸蛋白磷酸化变化；和（iv）P2X1 介导的细胞外 Ca(2+)内流。

结果

磷酸骨架修饰的 Ap(4)A 类似物抑制 P2Y(1)和 P2Y(12)，对这些受体没有激动剂活性。二硫修饰增加了对 P2Y(1)、P2Y(12)和血小板聚集的抑制作用，而氯亚甲基修饰增加了对 P2Y(12)和血小板聚集的抑制作用，但降低了对 P2Y(1)的抑制作用。将二硫和氯亚甲基修饰相结合增加了 P2Y(1)和 P2Y(12)的抑制作用。与 Ap(4)A 相比，每种修饰都降低了对 P2X1 的激动剂活性，而双重修饰则完全消除了 P2X1 的激动剂活性。

结论

与 Ap(4)A 相比，Ap(4)A 的四磷酸盐类似物对 P2X1 的活性降低，但抑制 P2Y(1)和 P2Y(12)，并以更高的效力抑制 ADP 诱导的血小板聚集。因此，具有双重受体选择性的二腺苷四磷酸盐类似物可能具有作为抗血小板药物的潜力。