Scanlon M N, Matsoukas J M, Franklin K J, Moore G J
Life Sci. 1984 Jan 23;34(4):317-21. doi: 10.1016/0024-3205(84)90618-0.
[Sar1, Tyr(Me)4]angiotensin II, synthesized by the solid phase method and purified by ion-exchange chromatography and reversed-phase HPLC, was found to inhibit the contractile response to angiotensin II in the rat isolated uterus and inhibit the pressor response to angiotensin II in the vagotomized ganglion-blocked rat. In the rat isolated uterus Schild plots gave a pA2 of 8.1, and a slope of 0.9 indicative of competitive inhibition. In the rat pressor assay, infusion of the analogue at a rate of 500ng/kg/min caused a parallel displacement of the dose-response curve to ANG II to the right. In contrast, the classical angiotensin inhibitor [Sar1, Ile8] ANG II appeared to demonstrate non-competitive inhibition in both the rat isolated uterus and the pressor assays. The phenolic hydroxyl of phenoxide anion of Tyr4 in angiotensin II appears to be critical for the activation of angiotensin receptors in smooth muscle. Alkylation of the tyrosine residue in angiotensin analogues provides a new route for the synthesis of potent competitive antagonists of angiotensin.
通过固相法合成并经离子交换色谱和反相高效液相色谱纯化得到的[Sar1, Tyr(Me)4]血管紧张素II，被发现可抑制大鼠离体子宫对血管紧张素II的收缩反应，并抑制迷走神经切断且神经节阻断的大鼠对血管紧张素II的升压反应。在大鼠离体子宫实验中，施尔德曲线得出pA2为8.1，斜率为0.9，表明为竞争性抑制。在大鼠升压实验中，以500ng/kg/min的速率输注该类似物导致血管紧张素II的剂量-反应曲线平行右移。相比之下，经典的血管紧张素抑制剂[Sar1, Ile8]血管紧张素II在大鼠离体子宫实验和升压实验中似乎均表现为非竞争性抑制。血管紧张素II中Tyr4的酚氧阴离子的酚羟基对于平滑肌中血管紧张素受体的激活似乎至关重要。血管紧张素类似物中酪氨酸残基的烷基化提供了一种合成强效血管紧张素竞争性拮抗剂的新途径。
