Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses.
Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses.
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13-氮杂前列腺酸类似物拮抗血小板和血管平滑肌中前列腺素介导的反应。
DOI：
10.1016/0006-2952(85)90258-8
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发表时间：
1985
影响因子：
5.8
通讯作者：
Feller,DR
中科院分区：
文献类型：
--
作者：
Huzoor-Akbar;Mukhopadhyay,A;Anderson,KS;Navran,SS;Romstedt,K;Miller,DD;Feller,DR
进行了研究，以检查有限系列的前列腺烷酸类似物抑制花生四烯酸（AA）和/或内过氧化物（U46619）介导的人血小板和大鼠主动脉的反应的药理学性质和立体化学要求。为了评估立体化学的作用，制备了一组13-氮杂丙烷酸（阿帕）和11 α-高-13-氮杂丙烷酸（HAPA）的反式和顺式异构体。每种前列腺烷酸类似物均以浓度依赖性方式（0.1至100 μM）阻断AA或U46619诱导的血小板聚集和分泌反应以及U46619介导的大鼠主动脉收缩。azaprostanoic acid类似物阻断了对两种血小板活化诱导剂的反应，其ic 50值范围为3.4 - 27.5μM。trans-APA作为AA或U46619诱导的5-羟色胺释放的拮抗剂的活性比其余类似物高约2- 3倍。这些类似物对U46619诱导的人血小板中5-羟色胺释放的抑制效力（ic 50; μM）的等级顺序为：反式-APA（3.4）>顺式-APA（8.9）=顺式-HAPA（8.7）=反式-HAPA（9.1）。阻断对AA和U46619的这些反应所需的前列腺烷酸类似物浓度相似，使用的最高浓度（100 μM）未改变人血小板制剂中AA诱导的丙二醛生成。阿帕和HAPA的异构体对U46619引起的大鼠血管收缩有同样的拮抗作用，其KB值为7.1 ~ 13.2 μM。每一个azaprostanoic酸类似物移动U46619在大鼠主动脉的浓度-反应曲线的权利，表明竞争型抑制。此外，偶氮前列腺素酸类似物（U 51605）是该制剂中U46619的更有效的竞争性拮抗剂，其平均pKB值为6.18。总之，结果表明：（1）阿帕的五元环扩展为六元环类似物（HAPA）导致在人血小板和大鼠血管平滑肌中保留了对U46619的有效抑制活性，（2）氮杂丙烷酸类似物的抗聚集和抗分泌作用是通过阻断对AA和U46619的反应介导的，而不是通过抑制AA代谢，（3）阿帕异构体的阻断活性是立体选择性的（反式>顺式），而HAPA异构体作为血小板功能抑制剂同样有效，（4）这些氮杂前列烷酸类似物在这两种组织中作为选择性内过氧化物（U46619）/血栓烷A2拮抗剂。
Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/ or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set oftrans- andcis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 μM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation withic50values ranging from 3.4 to 27.5μM.Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (ic50; μM) for these analogs against U46619-induced serotonin release in human platelets wastrans-APA (3.4) >cis-APA (8.9) =cis-HAPA (8.7) =trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 μM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-indueed contractions of rat vascular tissue, possessingKBvalues varying from 7.1 to 13.2 μM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKBvalue of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans>cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2antagonists in these two tissues.