Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist
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DOI：
10.1021/jm049715t
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发表时间：
2004-11-18
影响因子：
7.3
通讯作者：
Alterman, M
中科院分区：
文献类型：
--
作者：
Wan, YQ;Wallinder, C;Alterman, M
报道了第一种药物样选择性血管紧张素II AT（2）受体激动剂（21），其对AT（2）受体的Ki值为0.4 nM，对AT 1受体的Ki> 10 μ M。化合物21在口服给药后具有20-30%的生物利用度，并且在大鼠中的半衰期估计为4小时，其诱导神经突细胞的生长，刺激p42/p44（mapk），增强Sprague-Dawley大鼠中的体内十二指肠碱性分泌，并且降低麻醉的自发性高血压大鼠中的平均动脉血压。因此，肽模拟物21在选择性激活AT 2受体后发挥与内源性肽血管紧张素II相似的生物学应答。衍生自原型非选择性AT（1）/AT（2）受体激动剂L-162，313的化合物21将用作有价值的研究工具，使得能够更详细地研究AT 2受体的功能。
The first druglike selective angiotensin II AT(2) receptor agonist (21) with a K-i value of 0.4 nM for the AT(2) receptor and a K-i > 10 muM for the AT, receptor is reported. Compound 21, with a bioavailability of 20-30% after oral administration and a half-life estimated to 4 h in rat, induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhances in vivo duodenal alkaline secretion in Sprague-Dawley rats, and lowers the mean arterial blood pressure in anesthetized, spontaneously hypertensive rats. Thus, the peptidomimetic 21 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT2 receptor. Compound 21, derived from the prototype nonselective AT(1)/AT(2) receptor agonist L-162,313 will serve as a valuable research tool, enabling studies of the function of the AT2 receptor in more detail.