{"title":"[D-Met2, Pro5]脑啡肽[N1,5- β - d -2,3,4,6- o -四乙酰糖基]-酰胺和[D-Met2, Pro5]脑啡肽的合成及其抗伤活性","authors":"H Lin, S Shah, I K Reddy, B C Yoburn, S W Zito","doi":"","DOIUrl":null,"url":null,"abstract":"<p><p>Tetra-O-acetylgalactopyranosylamine and tetra-O-acetylglucopyranosylamine of D-Met2, Pro5 enkephalin were designed and synthesized to enhance their membrane penetration, biological activity and resistance to proteolytic hydrolysis. Three approaches to the synthesis were attempted, which lead to a new synthetic scheme with a higher yield and enhanced ease of purification. The improved procedure involved attaching the tetra-O-acetylglycopyranosylamine to a t-Boc-Gly-Phe-Pro-OH peptide, removing the t-Boc, and condensing it with t-Boc-Tyr-D-Met-OH. Biological evaluation in vivo showed that these acetylglycopyranosylamine derivatives bind to mu and delta opioid receptors in homogenate binding assays and possess analgesic activity. The analgesic potency was less than that of the parent compound D-Met2, Pro5 enkephalin. These acetylglycopyranosylamine derivatives showed enhanced lipophilicity compared to their parent compound by a partition coefficient study and they also showed greater membrane permeability, using the rabbit cornea as a model system. These derivatives also are resistant to hydrolytic enzymes as compared to the endogenous met-enkephalin when evaluated in homogenized iris-ciliary body and aqueous humor from rabbit eyes.</p>","PeriodicalId":11297,"journal":{"name":"Drug design and discovery","volume":"15 2","pages":"83-94"},"PeriodicalIF":0.0000,"publicationDate":"1997-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis and antinociceptive activity of [D-Met2, Pro5] enkephalin [N1,5-beta-D-2,3,4,6-O-tetraacetylglycosyl]--amide and [D-Met2, Pro5] enkephalinamide.\",\"authors\":\"H Lin, S Shah, I K Reddy, B C Yoburn, S W Zito\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Tetra-O-acetylgalactopyranosylamine and tetra-O-acetylglucopyranosylamine of D-Met2, Pro5 enkephalin were designed and synthesized to enhance their membrane penetration, biological activity and resistance to proteolytic hydrolysis. Three approaches to the synthesis were attempted, which lead to a new synthetic scheme with a higher yield and enhanced ease of purification. The improved procedure involved attaching the tetra-O-acetylglycopyranosylamine to a t-Boc-Gly-Phe-Pro-OH peptide, removing the t-Boc, and condensing it with t-Boc-Tyr-D-Met-OH. Biological evaluation in vivo showed that these acetylglycopyranosylamine derivatives bind to mu and delta opioid receptors in homogenate binding assays and possess analgesic activity. The analgesic potency was less than that of the parent compound D-Met2, Pro5 enkephalin. These acetylglycopyranosylamine derivatives showed enhanced lipophilicity compared to their parent compound by a partition coefficient study and they also showed greater membrane permeability, using the rabbit cornea as a model system. These derivatives also are resistant to hydrolytic enzymes as compared to the endogenous met-enkephalin when evaluated in homogenized iris-ciliary body and aqueous humor from rabbit eyes.</p>\",\"PeriodicalId\":11297,\"journal\":{\"name\":\"Drug design and discovery\",\"volume\":\"15 2\",\"pages\":\"83-94\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"1997-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug design and discovery\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug design and discovery","FirstCategoryId":"1085","ListUrlMain":"","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
设计合成了D-Met2, Pro5脑啡肽的四- o -乙酰半乳糖氨基乙胺和四- o -乙酰葡萄糖氨基乙胺,以提高它们的透膜性、生物活性和抗蛋白水解能力。尝试了三种合成方法,得到了一种收率更高、易于纯化的新合成方案。改进后的程序包括将四- o-乙酰甘氨酸氨基连接到t-Boc- gly - phe - pro - oh肽上,去除t-Boc,并与t-Boc- tyr - d - met - oh缩合。体内生物学评价表明,这些乙酰甘氨酰基氨基衍生物在均质结合实验中与阿片受体和阿片受体结合并具有镇痛活性。其镇痛效力低于母体化合物D-Met2, Pro5脑啡肽。通过分配系数研究,这些乙酰甘氨酰基氨基衍生物与母体化合物相比,表现出更强的亲脂性,并以兔角膜为模型系统显示出更大的膜通透性。在均质虹膜-睫状体和兔眼房水中进行评价时,与内源性的脑啡肽相比,这些衍生物也具有抗水解酶的能力。
Synthesis and antinociceptive activity of [D-Met2, Pro5] enkephalin [N1,5-beta-D-2,3,4,6-O-tetraacetylglycosyl]--amide and [D-Met2, Pro5] enkephalinamide.
Tetra-O-acetylgalactopyranosylamine and tetra-O-acetylglucopyranosylamine of D-Met2, Pro5 enkephalin were designed and synthesized to enhance their membrane penetration, biological activity and resistance to proteolytic hydrolysis. Three approaches to the synthesis were attempted, which lead to a new synthetic scheme with a higher yield and enhanced ease of purification. The improved procedure involved attaching the tetra-O-acetylglycopyranosylamine to a t-Boc-Gly-Phe-Pro-OH peptide, removing the t-Boc, and condensing it with t-Boc-Tyr-D-Met-OH. Biological evaluation in vivo showed that these acetylglycopyranosylamine derivatives bind to mu and delta opioid receptors in homogenate binding assays and possess analgesic activity. The analgesic potency was less than that of the parent compound D-Met2, Pro5 enkephalin. These acetylglycopyranosylamine derivatives showed enhanced lipophilicity compared to their parent compound by a partition coefficient study and they also showed greater membrane permeability, using the rabbit cornea as a model system. These derivatives also are resistant to hydrolytic enzymes as compared to the endogenous met-enkephalin when evaluated in homogenized iris-ciliary body and aqueous humor from rabbit eyes.