Nonpeptide Mimic of Bradykinin with Long-Acting Properties at the Bradykinin B2 Receptor

• DOI: 10.1124/mol.52.1.16
• Publication Date: 2018-01-08T20:27:27Z
• Authors: Ichiro Aramori; Junko Zenkoh; Noriyuki Morikawa; Masayuki Asano; Chie Hatori; Hiroe Sawai; Hiroshi Kayakiri; Shigeki Satoh; Takayuki Inoue; Yoshito Abe; Yuki Sawada; Tsuyoshi Mizutani; Noriaki Inamura; Kunio Nakahara; Hitoshi Kojo; Teruo Oku; Yoshitada Notsu
• Keywords: Bradykinin receptor

Kinins, members of a family peptides released from kininogens by the action kallikreins, exhibit variety biological activities including vasodilation, increased vascular permeability, contraction smooth muscle cells, and activation sensory neurons. However, investigation physiological actions kinins has been greatly hampered because its effects are curtailed rapid proteolysis in blood, lung, liver. We describe pharmacological characteristics novel nonpeptide bradykinin receptor agonist FR190997 (8-[2,6-dichloro-3-[<i>N</i>-[(<i>E</i>)-4-(<i>N</i>-methylcarbamoyl)cinnamidoacetyl]-<i>N</i>-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline). markedly stimulated phosphatidylinositol hydrolysis Chinese hamster ovary cells permanently expressing human B₂ receptor. The response was antagonized selective antagonist Hoe 140 (d-Arg-[hydroxyproline³,β-thienylalanine⁴,d-Tic⁷,Oic⁸]bradykinin). In competitive experiments using membranes prepared subtypes, showed high affinity binding to with IC₅₀ value 5.3 nm no for B₁ <i>In vivo</i>, mimics induces hypotensive responses rats prolonged duration. Therefore, is highly potent subtype-selective which displays intrinsic activity. This compound should represent powerful tool further physiology pathophysiology receptors.