Matsoukas J M, Agelis G, Hondrelis J, Yamdagni R, Wu Q, Ganter R, Smith J R, Moore D, Moore G J
Department of Chemistry, University of Patras, Greece.
J Med Chem. 1993 Apr 2;36(7):904-11. doi: 10.1021/jm00059a016.
Analogues of [Sar1]angiotensin II, Sarilesin (type I antagonist), and Sarmesin (type II antagonist) with L-azetidine-2-carboxylic acid (Aze) and L-pipecolic acid (Pip) at position 7 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus. Analogues of the superagonist [Sar1]ANGII with Aze or Pip at position 7 and sarcosine (Sar) or aminoisobutyric acid (Aib) at position 1 had high intrinsic activity in the rat isolated uterus assay (34-184%). Analogues of Sarilesin ([Sar1,Ile8]ANGII) with Aze or Pip at position 7 and Sar or Aib at position 1 retained high antagonist activity (pA2 = 7.1-8.3). Analogues of Sarmesin ([Sar1,Tyr-(OMe)4]ANGII) with Aze and Pip at position 7 had pA2 values of 7.4 and 6.5, respectively. [Aze7]-ANGII and [Pip7]ANGII had low activities (12% and 1%, respectively), and deletion of Sar at position 1 of Sarmesin analogues abolished binding (or affinity) as judged from pA2 values. Nuclear Overhauser effect (NOE) spectroscopy studies of [Sar1,Aze7]ANGII in DMSO-d6 have indicated a clustering of the three aromatic rings (Tyr, His, Phe) and proximity of Sar C alpha and Arg C delta protons to the Tyr/Phe ring protons. These data emphasize that replacement of Pro with the lower and higher homologs Aze and Pip does not greatly alter the structural requirements necessary for expression of agonist or antagonist activity, when sarcosine occupies position 1, but not when Asp occupies position 1, suggesting that there is an intimate relationship between the N-terminal and penultimate residues of the molecule in the biologically active conformation of the molecule.
已通过固相法制备了在第7位带有L-氮杂环丁烷-2-羧酸（Aze）和L-哌啶酸（Pip）的[Sar1]血管紧张素II类似物、Sarilesin（I型拮抗剂）和Sarmesin（II型拮抗剂），通过反相高效液相色谱法进行纯化，并在大鼠子宫中进行生物测定。在第7位带有Aze或Pip且在第1位带有肌氨酸（Sar）或氨基异丁酸（Aib）的超级激动剂[Sar1]ANGII类似物在大鼠离体子宫测定中具有高内在活性（34 - 184%）。在第7位带有Aze或Pip且在第1位带有Sar或Aib的Sarilesin（[Sar1,Ile8]ANGII）类似物保留了高拮抗活性（pA2 = 7.1 - 8.3）。在第7位带有Aze和Pip的Sarmesin（[Sar1,Tyr-(OMe)4]ANGII）类似物的pA2值分别为7.4和6.5。[Aze7]-ANGII和[Pip7]ANGII活性较低（分别为12%和1%），并且从pA2值判断，Sarmesin类似物第1位的Sar缺失会消除结合（或亲和力）。在氘代二甲亚砜（DMSO-d6）中对[Sar1,Aze7]ANGII进行的核Overhauser效应（NOE）光谱研究表明，三个芳香环（Tyr、His、Phe）聚集在一起，并且Sar Cα和Arg Cδ质子靠近Tyr/Phe环质子。这些数据强调，当肌氨酸占据第1位时，用较低和较高同系物Aze和Pip替代Pro不会极大地改变激动剂或拮抗剂活性表达所需的结构要求，但当Asp占据第1位时则不然，这表明在分子的生物活性构象中，分子的N端和倒数第二个残基之间存在密切关系。
