BIOCHEMICAL AND PHARMACOLOGICAL ACTIVITY OF ARENE-FUSED PROSTACYCLIN ANALOGS ON HUMAN PLATELETS
BIOCHEMICAL AND PHARMACOLOGICAL ACTIVITY OF ARENE-FUSED PROSTACYCLIN ANALOGS ON HUMAN PLATELETS
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DOI：
10.1016/0090-6980(94)90060-4
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发表时间：
1994-03-01
期刊：
影响因子：
--
通讯作者：
FUCHS, PL
中科院分区：
文献类型：
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作者：
JAKUBOWSKI, JA;UTTERBACK, BG;FUCHS, PL
人血小板已被用作测定系统来评估一组稳定的芳烃融合前列环素类似物的药理活性。前列环素 (PGI2) 是类二十烷酸家族的高活性成员，在生理条件下相对不稳定。前列环素最典型的活性是抑制血小板聚集和松弛血管平滑肌。这些活性在很大程度上是通过受体占据和腺苷酸环化酶激活后细胞内环AMP水平升高介导的。我们之前描述了一系列芳烃融合的前列环素类似物的合成，这些类似物在生理 pH 值的水介质中具有稳定性。其中几种化合物具有类前列环素活性，即与血小板前列环素受体竞争性结合、提高血小板内环磷酸腺苷水平并抑制人血小板聚集。特别是一种化合物 (11a) 证明了这些活性与 PGI2 相似，即血小板受体处的 Kd 为 3.7 nM，抑制血浆中胶原蛋白诱导的人血小板聚集的 IC50 为 2.9 nM。
Human platelets have been employed as an assay system to evaluate the pharmacological activity of a group of stable, arene-fused prostacyclin analogs. Prostacyclin (PGI2) is a highly active member of the eicosanoid family and is relatively unstable under physiological conditions. Prostacyclin's best characterized activities are those of inhibition of platelet aggregation and relaxation of vascular smooth muscle. These activities are mediated in large part via elevation of intracellular levels of cyclic AMP subsequent to receptor occupation and activation of adenylate cyclase. We previously described the synthesis of a series of arene-fused prostacyclin analogs with stability in aqueous media at physiological pH. Several of these compounds have prostacyclin-like activities, i.e., competitive binding at the platelet prostacyclin receptor, elevation of intraplatelet cyclic AMP levels and inhibition of human platelet aggregation. One compound in particular (11a) demonstrated these activities with potency similar to PGI2, i.e., Kd at platelet receptor of 3.7 nM and IC50 for inhibition of collagen-induced human platelet aggregation in plasma of 2.9 nM.