Nonpeptide Mimic of Bradykinin with Long-Acting Properties at the Bradykinin B₂Receptor

Abstract

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.

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Other examples of GPCR ligands exist where very slight structural modifications, such as addition or deletion of a simple methylene group, change antagonists to agonists at cholecystokinin (Aquino et al, 1996) and AT 1 receptors (Perlman et al, 1995), not withstanding the well known close structural similarity of the opiate ligands morphine and naloxone. In the case of FR190997, potent B 2 receptor agonist activity is demonstrated in vitro with a level of efficacy approaching BK itself, and in vivo FR190997 produces hypotension in rats (Aramori et al, 1997a). Although compounds like FR190997 may have therapeutic utility as antihypertensive or as cardioprotective agents, appropriate clinical testing remains.…”

“…Clearly, there is potential for kinin agonists, particularly B 2 receptor agonists, as novel cardioprotective agents; however, it is unclear whether proinflammatory effects would preclude their development (Aramori et al, 1997a;Heitsch, 2003).…”

“…FR190997 is a very interesting example of a nonpeptidyl structure exhibiting agonist activity at the B 2 receptor ( Fig. 2; Aramori et al, 1997a). FR190997 was derived chemically from, and bears close structural similarity to, a series of nonpeptide B 2 receptor antagonists (see FR173657, Fig.…”

Small-molecule agonists for the glucagon-like peptide 1 receptor

“…In recent years, smallmolecule agonists have been described, even for receptors for larger hormones like insulin, TPO, and EPO (18)(19)(20), but none of these receptors belong to the GPCR superfamily. Within the GPCRs, small-molecule agonists have been described, e.g., for the arginine vasopressin V-2 receptor, the somatostatin receptor, the bradykinin receptor, the cholecystokinin receptor, the angiotensin II receptor, and the growth hormone secretagogue receptor (21)(22)(23)(24)(25)(26). However, none of these GPCRs belong to the B family, and the natural ligands are all either fairly small or have a defined secondary structure.…”

Bradykinin B2and GPR100 receptors: a paradigm for receptor signal transduction pharmacology

“…The aim of the present study was to further characterize the pharmacology of the hGPR100, as compared with that of hB 2 R, by means of the peptide agonist BK, the nonpeptide B 2 receptor agonist FR190997 (8-[2,6-dichloro-3-[N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline) (Aramori et al, 1997), the human peptide relaxin 3 (Liu et al, 2003), and the B 2 receptor antagonist Icatibant (Hock et al, 1991).…”