Steven M. Seiler , Catherine L. Brassard , Marianne E. Federici , Jeffrey Romine , Nicholas A. Meanwell
{"title":"[3-[4-(4,5-二苯基-2-恶唑基)-5-恶唑基]苯氧基]乙酸(BMY 45778)是一种有效的非前列腺素类前列环素部分激动剂:对血小板聚集、腺苷酸环化酶、cAMP水平、蛋白激酶和伊洛前列素结合的影响","authors":"Steven M. Seiler , Catherine L. Brassard , Marianne E. Federici , Jeffrey Romine , Nicholas A. Meanwell","doi":"10.1016/S0090-6980(96)00138-4","DOIUrl":null,"url":null,"abstract":"<div><p>[3-(4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC<sub>50</sub> = 35 nM), rabbit (136 nM) and rat (1.3 μm) platelet aggregation. This compound activates adenylyl cyclase (ED<sup>50</sup>= 6−10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC<sub>50</sub>) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45 778 completely prevents [<sup>3</sup>H]Iloprost binding to platelet membranes (IC<sub>50</sub> = 7 nM). In whole platelets, BMY 45 778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP dependent protein (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonist, acts by stimulating prostacyclin (IP) receptors.</p></div>","PeriodicalId":20653,"journal":{"name":"Prostaglandins","volume":"53 1","pages":"Pages 21-35"},"PeriodicalIF":0.0000,"publicationDate":"1997-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0090-6980(96)00138-4","citationCount":"19","resultStr":"{\"title\":\"[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) is a potent non-prostanoid prostacyclin partial agonist: Effects on platelet aggregation, adenylyl cyclase, cAMP levels, protein kinase, and iloprost binding\",\"authors\":\"Steven M. Seiler , Catherine L. Brassard , Marianne E. Federici , Jeffrey Romine , Nicholas A. Meanwell\",\"doi\":\"10.1016/S0090-6980(96)00138-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>[3-(4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC<sub>50</sub> = 35 nM), rabbit (136 nM) and rat (1.3 μm) platelet aggregation. This compound activates adenylyl cyclase (ED<sup>50</sup>= 6−10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC<sub>50</sub>) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45 778 completely prevents [<sup>3</sup>H]Iloprost binding to platelet membranes (IC<sub>50</sub> = 7 nM). In whole platelets, BMY 45 778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP dependent protein (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonist, acts by stimulating prostacyclin (IP) receptors.</p></div>\",\"PeriodicalId\":20653,\"journal\":{\"name\":\"Prostaglandins\",\"volume\":\"53 1\",\"pages\":\"Pages 21-35\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1997-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1016/S0090-6980(96)00138-4\",\"citationCount\":\"19\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Prostaglandins\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0090698096001384\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Prostaglandins","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0090698096001384","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
[3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) is a potent non-prostanoid prostacyclin partial agonist: Effects on platelet aggregation, adenylyl cyclase, cAMP levels, protein kinase, and iloprost binding
[3-(4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy]acetic acid (BMY 45778) inhibits human (IC50 = 35 nM), rabbit (136 nM) and rat (1.3 μm) platelet aggregation. This compound activates adenylyl cyclase (ED50= 6−10 nM) and stimulates GTPase in human platelet membrane preparations. The potency (EC50) of BMY 45778 stimulating adenylyl cyclase is comparable to iloprost. However, maximal stimulation of GTPase by BMY 45778 is approximately half the iloprost-stimulated activity, and BMY 45778 limits the GTPase stimulation by iloprost suggesting that BMY 45778 is a partial agonist at the IP receptor. BMY 45 778 completely prevents [3H]Iloprost binding to platelet membranes (IC50 = 7 nM). In whole platelets, BMY 45 778 causes elevation of platelet cAMP levels (cAMP content doubles at 13 nM) and activation of the cAMP dependent protein (cAMP-protein kinase ratio is twice basal at 2 nM). BMY 45778 treatment of whole platelets also desensitizes the adenylyl cyclase activation by iloprost. These results indicate that BMY 45778, which is structurally different from prostacyclin and most prostacyclin agonist, acts by stimulating prostacyclin (IP) receptors.