Non-peptide Angiotensin Agonist
Non-peptide Angiotensin Agonist
复制标题
非肽血管紧张素激动剂
DOI：
10.1074/jbc.270.4.1493
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发表时间：
1995
期刊：
影响因子：
--
通讯作者：
T. Schwartz
中科院分区：
文献类型：
--
作者：
S. Perlman;H. Schambye;R. Rivero;W. Greenlee;S. Hjorth;T. Schwartz
g蛋白偶联型肽受体的非肽配体通常是拮抗剂，阿片系统除外。最近，人们观察到一组联苯咪唑衍生物在体内惊人地具有血管紧张素样活性。在转染了大鼠AT1受体（这些化合物的原型）的COS-7细胞中，L-162,313刺激磷酸肌苷水解，EC为33±11 nM。该化合物对COS-7细胞的最大反应是血管紧张素II的50%，而在稳定转染的中国仓鼠卵巢细胞中仅为3%。L-162,313的激动作用被at1特异性拮抗剂L-158,809阻断，在未转染的细胞中未观察到。在中国仓鼠卵巢细胞中，l - 162313对血管紧张素刺激的磷酸肌苷水解具有不可克服的拮抗剂作用。与先前测试的非肽配体相比，L-162,313与非洲爪蟾AT1受体结合具有相当高的亲和力。在人受体中，发现L-162,313的结合不受跨膜段III和VII点突变的影响，这损害了联苯咪唑拮抗剂的结合。人类和大鼠受体胞外结构域的替换会破坏血管紧张素II的结合，但不会影响L-162,313的结合。结果表明，联苯咪唑类化合物可作为AT1受体的高亲和力部分激动剂。这些化合物与受体的分子相互作用似乎既不同于结构相似的非肽拮抗剂，也不同于它们的功能对应物肽激动剂。
Non-peptide ligands for peptide receptors of the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells transfected with the rat AT1 receptor a prototype of these compounds, L-162,313 stimulated phosphoinositide hydrolysis with an EC of 33 ± 11 nM. The maximal response to the compound was 50% of that of angiotensin II in COS-7 cells but only 3% in stably transfected Chinese hamster ovary cells. The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells. In Chinese hamster ovary cells, L-162,313 also acted as an insurmountable antagonist of the angiotensin stimulated phosphoinositide hydrolysis. In contrast to previously tested non-peptide ligands, L-162,313 bound with reasonably high affinity to the Xenopus laevis AT1 receptor. In the human receptor, the binding of L-162,313 was found to be unaffected by point mutations in transmembrane segments III and VII, which impaired the binding of biphenylimidazole antagonists. Substitutions in the extracellular domains of the human and rat receptor, which impaired the binding of angiotensin II, did not affect the binding of L-162,313. It is concluded that a subset of biphenylimidazole compounds can act as high affinity partial agonists on the AT1 receptor. These compounds have molecular interactions with the receptor which appear to differ both from that of the structurally similar non-peptide antagonists and from that of their functional counterpart, the peptide agonist.
影响因子：
3.5
作者：
HORTON, RM;HUNT, HD;PEASE, LR
通讯作者：
PEASE, LR