（去天冬氨酸1）血管紧张素I作为（去天冬氨酸1）血管紧张素II（“血管紧张素III”）前体的合成与评估。

Synthesis and evaluation of (Des-Asp1)angiotensin I as a precursor for (Des-Asp1)angiotensin II ("Angiotensin III").

作者信息

Tsai B S, Peach M J, Khosla M C, Bumpus F M

出版信息

J Med Chem. 1975 Dec;18(12):1180-3. doi: 10.1021/jm00246a002.

Abstract

The nonapeptide [des-Asp1]angiotensin I (IV), synthesized by Merrifield's solid-phase procedure, was tested as a possible substrate for the converting enzymes from porcine lung and plasma. IV, [des-Asp1]angiotensin II (III), [des-(Asp1,Arg2)]angiotensin II (V), [des-(Asp1,Arg2,Val3)]angiotensin II (VI), [Sar1,Ile8]angiotensin II (VII), and [des-Asp1,Ile8]angiotensin II (VIII) possessed 0.5, 20, 2, 0 less than 0.1, and less than 0.01% of the inotropic activity (rabbit atria), 1, 15, 5, 0, 3, and 0% secretory activity of the cat adrenal medulla, and 0.0, 150, 0.5, 3, and 10% of the adrenal steroidogenic activity of angiotensin II, respectively. When tested for their antagonistic activity in the above tissues, only VII and VIII were found to inhibit responses to angiotensin II. The pA2 values for VII and VIII were 8.31 and 10.0 in the adrenal cortex and 9.31 and 9.16 in the adrenal medulla, respectively. All these peptides were also tested as product inhibitors for the plasma and lung converting enzymes. With the plasma enzyme, the ID50 values were II, 1.6 X 10(-4) M; III, 5 X 10(-5) M; V, 1.2 X 10(-4) M; VI 5 X 10(-4) M; VII 5 X 10(-5) M; VIII, 5 X 10(-4) M. Thus, IV is a good substrate for converting enzymes from lung and plasma while all other compounds were inhibitors of these enzymes. The most potent inhibitors of converting enzyme were III followed by VII and VIII. With the exception of II and III, all the other analogs had very low intrinsic activities, per se. These results suggest (a) an alternate pathway for the formation of heptapeptide III, viz., by the action of converting enzyme on the nonapeptide IV, and (b) that III may also be acting as inhibitor of the converting enzyme by the feedback mechanism.

摘要

采用梅里菲尔德固相法合成的九肽[去天冬氨酸1]血管紧张素I（IV），被作为猪肺和血浆中转化酶的潜在底物进行了测试。IV、[去天冬氨酸1]血管紧张素II（III）、[去（天冬氨酸1，精氨酸2）]血管紧张素II（V）、[去（天冬氨酸1，精氨酸2，缬氨酸3）]血管紧张素II（VI）、[Sar1，Ile8]血管紧张素II（VII）和[去天冬氨酸1，Ile8]血管紧张素II（VIII）的变力活性（兔心房）分别为血管紧张素II的0.5%、20%、2%、低于0.1%、低于0.01%；猫肾上腺髓质的分泌活性分别为1%、15%、5%、0%、3%、0%；肾上腺类固醇生成活性分别为0.0%、150%、0.5%、3%、10%。在上述组织中测试它们的拮抗活性时，仅发现VII和VIII能抑制对血管紧张素II的反应。VII和VIII在肾上腺皮质中的pA2值分别为8.31和10.0，在肾上腺髓质中分别为9.31和9.16。所有这些肽还作为血浆和肺转化酶的产物抑制剂进行了测试。对于血浆酶，半数抑制浓度（ID50）值分别为：II，1.6×10⁻⁴M；III，5×10⁻⁵M；V，1.2×10⁻⁴M；VI，5×10⁻⁴M；VII，5×10⁻⁵M；VIII，5×10⁻⁴M。因此，IV是肺和血浆中转化酶的良好底物，而所有其他化合物都是这些酶的抑制剂。转化酶最有效的抑制剂是III，其次是VII和VIII。除II和III外，所有其他类似物本身的内在活性都非常低。这些结果表明：（a）七肽III的形成存在一条替代途径，即通过转化酶对九肽IV的作用；（b）III也可能通过反馈机制作为转化酶的抑制剂发挥作用。