Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications.
Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications.
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血管紧张素 II 的新型环状类似物在位置 5 和位置 7 之间发生环化：构象和生物学意义。
DOI：
10.1021/jm9507744
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Marshall,GR
中科院分区：
文献类型：
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作者：
Zhang,WJ;Nikiforovich,GV;Perodin,J;Richard,DE;Escher,E;Marshall,GR
为了研究血管紧张素II(Asp-Arg-Val-Tyr-Val/Ile-His-Pro-Phe，AII)分子识别的构象特征，我们合成了几个位于第5位和第7位之间的AII环类似物，并进行了生物测试。合成的类似物为Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Pen7)-Phe8(3)，Sar1-Arg2-Val3-Tyr4-cyclo(Asp5-His6-Apt7)-Phe8(4)，Sar1-Arg2-Val3-Tyr4-cyclo(Glu5-His6-Apt7)-Phe8(5)，Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpt7)-Phe8(6)，Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpc7)-Phe8(7)，Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpt7)-Phe8(8)，和Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpc7)-Phe8(9)，，其中APT代表4-氨基-反式脯氨酸，MPT和Mpc分别代表4-巯基-反式和顺式-脯氨酸。化合物(9)与AT-1受体有较好的亲和力，AKD=20 nM。在功能分析中，它表现出弱部分激动剂的特征，相对亲和力是AII的0.26%，内在效力αE为0.42.分子模拟对这一发现提出了可能的解释： 化合物9相对较强的结合和较弱的部分兴奋活性是由于只与两个重要功能基团的AT-1受体相互作用所致，即His6和Phe8残基的侧链。
To study the conformational features of molecular recognition of angiotensin II (Asp-Arg-Val-Tyr-Val/Ile-His-Pro-Phe, AII), the synthesis and biological testing of several cyclic analogs of AII cyclized between positions 5 and 7 have been performed. The synthesized analogs were Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Pen7)-Phe8(3), Sar1-Arg2-Val3-Tyr4-cyclo(Asp5-His6-Apt7)-Phe8(4), Sar1-Arg2-Val3-Tyr4-cyclo(Glu5-His6-Apt7)-Phe8(5), Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpt7)-Phe8(6), Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpc7)-Phe8(7), Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpt7)-Phe8(8), and Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpc7)-Phe8(9), where Apt stands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto-trans- and -cis-prolines, respectively. Compound(9)showed good affinity at AT-1 receptors, namely aKD= 20 nM. In functional assays, it showed the characteristics of a weak partial agonist with a relative affinity of 0.26% of that for AII and an intrinsic efficacy, αE, of 0.42. Molecular modeling suggested a possible explanation for this finding: the relatively strong binding and the weak partial agonistic activity of compound9are due to interaction with AT-1 receptor of only two functionally important groups, namely, the side chains of the His6and Phe8residues.