Mukhopadhyay A, Anderson K S, Navran S S, Romstedt K, Miller D D, Feller D R
Biochem Pharmacol. 1985 Mar 1;34(5):641-7. doi: 10.1016/0006-2952(85)90258-8.
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 of trans- and cis-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 microM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with IC50 values ranging from 3.4 to 27.5 microM. 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; microM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) greater than 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 microM) 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-induced contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 microM. 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 pKB value 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 greater than 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 A2 antagonists in these two tissues.
开展了多项研究，以考察一系列有限的前列腺酸类似物对人血小板和大鼠主动脉中花生四烯酸（AA）和/或内过氧化物（U46619）介导的反应的药理特性和立体化学要求。为评估立体化学的作用，制备了一组13-氮杂前列腺酸（APA）和11a-高-13-氮杂前列腺酸（HAPA）的反式和顺式异构体。每种前列腺酸类似物均以浓度依赖性方式（0.1至100 microM）阻断血小板中AA或U46619诱导的聚集和分泌反应，以及U46619介导的大鼠主动脉收缩。氮杂前列腺酸类似物阻断对两种血小板激活诱导剂的反应，IC50值范围为3.4至27.5 microM。作为AA或U46619诱导的5-羟色胺释放的拮抗剂，反式APA的活性比其余类似物高约2至3倍。这些类似物对人血小板中U46619诱导的5-羟色胺释放的抑制效力（IC50； microM）的顺序为：反式APA（3.4）大于顺式APA（8.9）=顺式HAPA（8.7）=反式HAPA（9.1）。阻断对AA和U46619这些反应所需的前列腺酸类似物浓度相似，并且所使用的最高浓度（1oomicroM）未改变人血小板制剂中AA诱导的丙二醛生成。相比之下，APA和HAPA的异构体作为U46619诱导的大鼠血管组织收缩的拮抗剂具有同等活性，KB值在7.1至13.2 microM之间变化。每种氮杂前列腺酸类似物均使大鼠主动脉中U46619的浓度-反应曲线右移，表明为竞争性抑制类型。此外，氮杂前列腺酸类似物（U51605）在该制剂中是U46619更有效的竞争性拮抗剂，平均pKB值为6.18。总之，结果表明：（1）将APA的五元环扩展为六元环类似物（HAPA）导致对人血小板和大鼠血管平滑肌中U46619保持强效抑制活性；（2）氮杂前列腺酸类似物的抗聚集和抗分泌作用通过阻断对AA和U46619的反应介导，而非通过抑制AA代谢；（3）APA异构体的阻断活性具有立体选择性（反式大于顺式），而HAPA异构体作为血小板功能抑制剂同样有效；以及（4）这些氮杂前列腺酸类似物在这两种组织中作为选择性内过氧化物（U46619）/血栓素A2拮抗剂起作用。
