Nonpeptide mimic of bradykinin with long-acting properties

Kinins, members of a family of peptides released from kininogens by the act ion of kallikreins, have been implicated in a variety of biological activit ies including vasodilation, increased vascular permeability, contraction of smooth muscle cells and activation of sensory neurons. However, investigat ion of the physiological actions of kinins have been greatly hampered becau se its effects are curtailed by rapid proteolytic degradation. We examined the pharmacological characteristics of the first nonpeptide bradykinin rece ptor agonist 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl ]-N-methyl-amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (FR19099 7). FR190997, whose structure is quite different from the natural peptide l igand, but is similar to the nonpeptide antagonists FR165649, FR167344 and FR173657, potently and selectively interacts with the human B-2 receptor an d markedly stimulates inositol phosphate formation in transfected Chinese h amster ovary (CHO) cells. FR190997 induces concentration-dependent contract ion of isolated guinea pig ileum. In vivo, FR190997 mimics the biological a ction of bradykinin and induces hypotensive responses in rats with prolonge d duration, presumably as a consequence of its resistance to proteolytic de gradation. Therefore, FR190997 is a highly potent and subtype-selective non peptide agonist which displays high intrinsic activity at the bradykinin B- 2 receptor. This compound represents a powerful tool for further investigat ion of the physiology and pathophysiology of bradykinin receptors. (C) 1999 Elsevier Science B.V. All rights reserved.