Bradykinin analogs containing 4-amino-2-benzazepin-3-one the scaffold at the C-terminus
Bradykinin analogs containing 4-amino-2-benzazepin-3-one the scaffold at the C-terminus
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DOI：
10.1002/psc.827
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发表时间：
2007-03-01
影响因子：
2.1
通讯作者：
Tourwe, D.
中科院分区：
文献类型：
--
作者：
Ballet, S.;De Wachter, R.;Tourwe, D.
缓激肽（BK）B-2亚型受体的高亲和力肽配体已显示采用C-末端四肽（H-Arg（1）-Pro（2）-Pro（3）-Gly（4）-Phe（5）-Ser（6）-Pro（7）-Phe（8）-Arg（9）-OH）的转角构象。我们研究了用4-氨基-1，2，4，5-四氢-2-苯并氮杂卓-3-酮模板（阿坝）替换BK中的Pro（7）-Phe（8）二肽部分或HOE 140中的D-Tic（7）-Oic（8）亚基（H-D-Arg（0）-Arg（1）-Pro（2）-Hyp（3）-Gly（4）-Thi（5）-Ser（6）-D-TiC 7-Oic（8）-Arg（9）-OH）。对人B2受体的结合研究表明BK类似物的亲和力与模板采用β-转角构象的倾向之间存在相关性。含有HOE 140类似物BK 10的L-螺-Aba-Gly具有最佳亲和力，这与该模板的已知转向诱导特性相关。所有化合物在高达10 μ M浓度下都不改变表达B-2的CHO细胞中的基础肌醇磷酸（IP）输出。豚鼠回肠平滑肌收缩试验证实了其拮抗特性。新的氨基苯并氮杂卓酮（阿坝）取代的BK类似物被发现是可克服的拮抗剂。版权所有（c）2007欧洲肽协会和约翰威利父子有限公司。
High affinity peptide ligands for the bradykinin (BK) B-2 subtype receptor have been shown to adopt a turn conformation of the C-terminal tetrapeptide (H-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)-OH). We investigated the replacement of the Pro(7)-Phe(8) dipeptide moiety in BK or the D-Tic(7)-Oic(8) subunit in HOE140 (H-D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-TiC7-Oic(8)-Arg(9)-OH) by 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one templates (Aba). Binding studies to the human B2 receptor showed a correlation between the affinities of the BK analogs and the propensity of the templates to adopt a beta-turn conformation. The L-spiro-Aba-Gly containing HOE140 analog BK10 has the best affinity, which correlates with the known turn-inducing property of this template. All the compounds did not modify basal inositolphosphate (IP) output in B-2-expressing CHO cells up to 10 mu m concentration. The antagonist proper-ties were confirmed by the guinea pig ileum smooth muscle contractility assay. The new amino-benzazepinone (Aba) substituted BK analogs were found to be surmountable antagonists. Copyright (c) 2007 European Peptide Society and John Wiley & Sons, Ltd.