Analogs of galanin (1-16) modified in positions 1-3 as ligands to rat hypothalamic galanin receptors.

C Rivera Baeza, K Kask, U Langel, T Bartfai, A Undén
{"title":"Analogs of galanin (1-16) modified in positions 1-3 as ligands to rat hypothalamic galanin receptors.","authors":"C Rivera Baeza,&nbsp;K Kask,&nbsp;U Langel,&nbsp;T Bartfai,&nbsp;A Undén","doi":"10.3891/acta.chem.scand.48-0434","DOIUrl":null,"url":null,"abstract":"<p><p>Structure-activity relationship (SAR) studies have revealed that the first three residues of galanin (Gly1-Trp2-Thr3) are of critical importance for high-affinity binding to the galanin receptor. Furthermore degradation studies have shown that galanin is easily cleaved to yield inactive fragments in rat hypothalamus (t1/2 = 100 min). To obtain galanin receptor ligands with long-lasting biological activity the amino-terminus of galanin must be protected. We have therefore synthesized analogs of rat galanin(1-16) carrying modifications at the three amino-termini of galanin. All modifications of the peptide backbone flanking Trp2 as in the analogs [N-Me-Trp2]-galanin(1-16), [Tcc2]-galanin-(1-16), (Trp2-psi[CH2NH]-Thr3)-galanin-(1-16) produced a dramatic loss of affinity toward the galanin receptor. [N-Me-Thr3]-galanin(1-16) was the most active of the peptide backbone modified analogs (KD = 997 +/- 1 nM). Modifications of the indole ring in Trp2 ([For-Trp2]-galanin-(1-16), [Tcc2]-galanin-(1-16)) yielded analogs which, at concentrations up to 10 microM, did not displace [125I]galanin binding. N-Methylation of Gly1 by the introduction of sarcosine ([Sar1]-galanin(1-16)) did not significantly affect the ligand-binding properties of galanin(1-16) (KD = 8.7 +/- 0.1 nM).</p>","PeriodicalId":76966,"journal":{"name":"Acta chemica Scandinavica (Copenhagen, Denmark : 1989)","volume":"48 5","pages":"434-8"},"PeriodicalIF":0.0000,"publicationDate":"1994-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"7","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta chemica Scandinavica (Copenhagen, Denmark : 1989)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3891/acta.chem.scand.48-0434","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 7

Abstract

Structure-activity relationship (SAR) studies have revealed that the first three residues of galanin (Gly1-Trp2-Thr3) are of critical importance for high-affinity binding to the galanin receptor. Furthermore degradation studies have shown that galanin is easily cleaved to yield inactive fragments in rat hypothalamus (t1/2 = 100 min). To obtain galanin receptor ligands with long-lasting biological activity the amino-terminus of galanin must be protected. We have therefore synthesized analogs of rat galanin(1-16) carrying modifications at the three amino-termini of galanin. All modifications of the peptide backbone flanking Trp2 as in the analogs [N-Me-Trp2]-galanin(1-16), [Tcc2]-galanin-(1-16), (Trp2-psi[CH2NH]-Thr3)-galanin-(1-16) produced a dramatic loss of affinity toward the galanin receptor. [N-Me-Thr3]-galanin(1-16) was the most active of the peptide backbone modified analogs (KD = 997 +/- 1 nM). Modifications of the indole ring in Trp2 ([For-Trp2]-galanin-(1-16), [Tcc2]-galanin-(1-16)) yielded analogs which, at concentrations up to 10 microM, did not displace [125I]galanin binding. N-Methylation of Gly1 by the introduction of sarcosine ([Sar1]-galanin(1-16)) did not significantly affect the ligand-binding properties of galanin(1-16) (KD = 8.7 +/- 0.1 nM).

甘丙氨酸(1-16)类似物在1-3位修饰为大鼠下丘脑甘丙氨酸受体的配体。
构效关系(SAR)研究表明,甘丙氨酸的前三个残基(Gly1-Trp2-Thr3)对于与甘丙氨酸受体的高亲和力结合至关重要。此外,降解研究表明,丙氨酸很容易在大鼠下丘脑(t1/2 = 100 min)中裂解产生无活性片段。为了获得具有持久生物活性的丙氨酸受体配体,必须保护丙氨酸的氨基末端。因此,我们合成了大鼠丙氨酸(1-16)的类似物,在丙氨酸的三个氨基末端进行了修饰。在类似物[N-Me-Trp2]-甘丙氨酸(1-16),[Tcc2]-甘丙氨酸-(1-16),(Trp2-psi[CH2NH]- thr3)-甘丙氨酸-(1-16)中,对Trp2侧肽主链的所有修饰都会导致对甘丙氨酸受体的亲和力急剧下降。[N-Me-Thr3]-甘丙氨酸(1-16)是肽骨架修饰类似物中活性最高的(KD = 997 +/- 1 nM)。修饰Trp2中的吲哚环([For-Trp2]-丙氨酸-(1-16),[Tcc2]-丙氨酸-(1-16))产生类似物,在浓度高达10微米时,不取代[125I]丙氨酸结合。引入肌氨酸([Sar1]-甘丙氨酸(1-16))对Gly1的n -甲基化没有显著影响甘丙氨酸(1-16)的配体结合性能(KD = 8.7 +/- 0.1 nM)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信