Aramori I, Zenkoh J, Morikawa N, Asano M, Hatori C, Sawai H, Kayakiri H, Satoh S, Inoue T, Abe Y, Sawada Y, Mizutani T, Inamura N, Nakahara K, Kojo H, Oku T, Notsu Y
Molecular Biological Research Laboratory, Fujisawa Pharmaceutical Co., Ltd., Tsukuba, Japan.
Mol Pharmacol. 1997 Jul;52(1):16-20. doi: 10.1124/mol.52.1.16.
Kinins, members of a family of peptides released from kininogens by the action of kallikreins, exhibit a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells, and activation of sensory neurons. However, investigation of the physiological actions of kinins has been greatly hampered because its effects are curtailed by rapid proteolysis in blood, lung, and liver. We describe the pharmacological characteristics of a novel nonpeptide bradykinin receptor agonist FR190997 (8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoli ne). FR190997 markedly stimulated phosphatidylinositol hydrolysis in Chinese hamster ovary cells permanently expressing the human bradykinin B2 receptor. The response of phosphatidylinositol hydrolysis was antagonized by the B2 receptor selective antagonist Hoe 140 (D-Arg-[hydroxyproline3,beta-thienylalanine4,D-Tic7,++ +Oic8]bradykinin). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the human bradykinin receptor subtypes, FR190997 showed a high affinity binding to the B2 receptor with IC50 value of 5.3 nM and no binding affinity for the B1 receptor. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity. This compound should represent a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.
激肽是激肽释放酶作用于激肽原后释放的一类肽家族成员，具有多种生物学活性，包括血管舒张、血管通透性增加、平滑肌细胞收缩以及感觉神经元激活。然而，激肽生理作用的研究受到极大阻碍，因为其作用会因在血液、肺和肝脏中的快速蛋白水解而受到限制。我们描述了一种新型非肽缓激肽受体激动剂FR190997（8-[2,6-二氯-3-[N-[(E)-4-(N-甲基氨基甲酰基)肉桂酰胺基乙酰基]-N-甲基氨基]苄氧基]-2-甲基-4-(2-吡啶甲氧基)喹啉）的药理学特性。FR190997能显著刺激永久表达人缓激肽B2受体的中国仓鼠卵巢细胞中的磷脂酰肌醇水解。磷脂酰肌醇水解反应可被B2受体选择性拮抗剂Hoe 140（D-精氨酸-[羟脯氨酸3，β-噻吩丙氨酸4，D-噻唑烷-4-羧酸7，8-氧代异亮氨酸8]缓激肽）拮抗。在使用表达人缓激肽受体亚型的中国仓鼠卵巢细胞膜进行的竞争性实验中，FR190997对B2受体显示出高亲和力结合，IC50值为5.3 nM，对B1受体无结合亲和力。在体内，FR190997模拟缓激肽的生物学作用，并在大鼠中诱导持续时间较长的降压反应。因此，FR190997是一种高效且亚型选择性的非肽激动剂，具有高内在活性。该化合物应是进一步研究缓激肽受体生理学和病理生理学的有力工具。
