血管紧张素II激动剂与I型拮抗剂之间主链结构的差异。

Differences in backbone structure between angiotensin II agonists and type I antagonists.

作者信息

Matsoukas J M, Agelis G, Wahhab A, Hondrelis J, Panagiotopoulos D, Yamdagni R, Wu Q, Mavromoustakos T, Maia H L, Ganter R

机构信息

Department of Chemistry, University of Patras, Greece.

出版信息

J Med Chem. 1995 Nov 10;38(23):4660-9. doi: 10.1021/jm00023a005.

DOI:10.1021/jm00023a005

PMID:7473593

Abstract

Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(gamma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus, and their backbone conformational properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar1,HSer-(gamma-OMe)8]ANGII, [HSer(gamma-OMe)8]ANGII, [Des1,HSer(gamma-OMe)8]ANGII, [Sar1,Nva(delta-OMe)8]-ANGII, and [Des1,Nva(delta-OMe)8]ANGII had, respectively, the following antagonist activities, pA2: 7.6, 7.5, < 6.0, 7.1, and 6.9. Analogs of [Sar1]ANGII with delta-hydroxy-L-norvaline [Nva(delta-OH)], delta-methoxy-L-norvaline [Nva(delta-OMe)], 4'-carboxyphenylalanine [Phe(4'-COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(delta-OH)4]ANGII, [Aib1,Nva(delta-OMe)4]ANGII, [Sar1,DL-Phe(4'-COOH)4]ANGII, and [Sar1,DL-Phe(4'-CF3)4]ANGII had, respectively, agonist activities as follows: 4%, 1.5%, 3%, < 0.1%, and < 0.1%. These data emphasize that replacement of Ile8 in Sarilesin with the higher homologs HSer(gamma-OMe) and Nva(delta-OMe) does not greatly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [Sar1]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be replaced by any negatively charged or electronegative group. Conformational investigation of the ANGII type I antagonists [HSer(gamma-OMe)8]ANGII and [Sar1Nva(delta-OMe)8]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found in ANGII and [Sar1]ANGII (J. Biol. Chem. 1994, 269, 5303) is not present in type I antagonists, providing for the first time an important conformational difference between angiotensin II agonists and type I antagonists.

摘要

通过固相法制备了8位带有O-甲基-L-高丝氨酸[HSer(γ-OMe)]和δ-甲氧基-L-正缬氨酸[Nva(δ-OMe)]的I型血管紧张素II拮抗剂，经反相高效液相色谱法纯化后在大鼠子宫中进行生物活性测定，并通过核Overhauser效应（NOE）光谱研究了它们的主链构象性质。[Sar1,HSer-(γ-OMe)8]ANGII、[HSer(γ-OMe)8]ANGII、[Des1,HSer(γ-OMe)8]ANGII、[Sar1,Nva(δ-OMe)8]-ANGII和[Des1,Nva(δ-OMe)8]ANGII分别具有以下拮抗剂活性，pA2值为：7.6、7.5、<6.0、7.1和6.9。还通过固相法制备了4位带有δ-羟基-L-正缬氨酸[Nva(δ-OH)]、δ-甲氧基-L-正缬氨酸[Nva(δ-OMe)]、4'-羧基苯丙氨酸[Phe(4'-COOH)]和4'-(三氟甲基)苯丙氨酸[Phe(4'-CF3)]的[Sar1]ANGII类似物，并在大鼠子宫中进行生物活性测定。[Sar1,Nva(δ-OH)4]ANGII、[Aib1,Nva(δ-OMe)4]ANGII、[Sar1,DL-Phe(4'-COOH)4]ANGII和[Sar1,DL-Phe(4'-CF3)4]ANGII分别具有以下激动剂活性：4%、1.5%、3%、<0.1%和<0.1%。这些数据表明，用更高的同系物HSer(γ-OMe)和Nva(δ-OMe)取代Sarilesin中的Ile8不会极大地改变I型拮抗剂活性表达所需的结构要求，而用羧酸盐或三氟甲基取代[Sar1]ANGII中的酪氨酸羟基会使活性丧失，这表明酪氨酸盐药效基团不能被任何带负电荷或电负性的基团取代。通过一维NOE光谱对二甲基亚砜中的I型血管紧张素II拮抗剂[HSer(γ-OMe)8]ANGII和[Sar1Nva(δ-OMe)8]ANGII进行构象研究发现，在血管紧张素II和[Sar1]ANGII中发现的Tyr-Ile-His弯曲构象性质（《生物化学杂志》1994年，269卷，5303页）在I型拮抗剂中不存在，这首次揭示了血管紧张素II激动剂和I型拮抗剂之间重要的构象差异。