选择性非肽类血管紧张素 II 型受体激动剂的研发。
Development of selective non-peptide angiotensin II type 2 receptor agonists.
机构信息
Department of Medicinal Chemistry, BMC, Uppsala University, Uppsala, Sweden.
出版信息
J Renin Angiotensin Aldosterone Syst. 2010 Mar;11(1):57-66. doi: 10.1177/1470320309347790. Epub 2009 Oct 30.
The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT( 1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 with a K(i) value of 0.4 nM for the AT( 2) receptor and a K(i) > 10 microM for the AT(1) receptor 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 anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.
本文介绍了第一个类似药物的选择性血管紧张素 II 型 2（AT(2)）受体激动剂（22）的开发，该激动剂源自非选择性血管紧张素 II 型 1（AT(1)）受体/AT(2)受体激动剂 L-162,313。化合物 22 对 AT(2)受体的 K(i)值为 0.4 nM，对 AT(1)受体的 K(i)值> 10 microM，它能诱导神经细胞突起生长，刺激 p42/p44（mapk），增强 Sprague-Dawley 大鼠体内十二指肠碱性分泌，并降低麻醉自发性高血压大鼠的平均动脉血压。因此，这种拟肽 22 在选择性激活 AT(2)受体后，会产生与内源性肽血管紧张素 II 相似的生物学反应。此外，化合物 22 经口服给药后的生物利用度为 20-30%，在大鼠体内的半衰期估计为 4 小时。因此，化合物 22 将成为一种有价值的研究工具，可更详细地研究 AT(2)受体的功能。
Zotero 插件