title: Structure-activity relationships of novel peptide agonists of the human bradykinin B2 receptor.
abstract: The nonapeptide bradykinin (BK) is involved in the genesis of inflammation, edema and in pain mediation. As such, much effort has gone into the development of peptide/non-peptide antagonists to counteract these processes. However, there is an increasing awareness of the potential value of chemically stable BK agonists in the treatment of diabetes and cardiovascular diseases. In this study, a structure-activity relationship study of BK was performed to develop potent and stable peptide mimetics active at the human B2 receptors (hB2R). Twenty-three analogues were produced with substitutions at positions 1, 3, 5, 7, 8 and/or 9 of BK. In vitro binding (on transiently transfected HEK-293T cells) and biological activities (vasomotricity tests on human umbilical veins, MAPK assays on HEK-293T cells) of novel BK peptide derivatives at hB2R were determined alongside with previously reported synthetic agonists (e.g. RMP-7, JMV1609, FR190997). Some peptides were also tested in vivo in rats and rabbits using blood pressure assays. Two compounds, [Hyp(3), Thi(5), Cha(8)]-BK and [Hyp(3), Thi(5), (N)Chg(7), Thi(8)]-BK, exhibited equivalent (or even greater) in vitro affinities and potencies to BK at the naturally expressed and recombinant hB2R. Their potency and duration of action in vivo were highly superior to BK, thus inferring that they can withstand intravascular proteolysis. These novel compounds show promise as candidates for investigating the pharmacology of BK receptors and developing potential therapeutical applications.
authors.affiliation: Department of Pharmacology, Université de Sherbrooke, Québec, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Bélanger
authors.forename: Veronica
authors.initials: V
authors.lastname: Bovenzi
authors.forename: Jérome
authors.initials: J
authors.lastname: Côté
authors.forename: Witold
authors.initials: W
authors.lastname: Neugebauer
authors.forename: Muriel
authors.initials: M
authors.lastname: Amblard
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
authors.forename: Bernard
authors.initials: B
authors.lastname: Lammek
authors.forename: Martin
authors.initials: M
authors.lastname: Savard
authors.forename: Fernand
authors.initials: F
authors.lastname: Gobeil
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D001920:Bradykinin / Q000737:chemistry*; D002460:Cell Line; D006801:Humans; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043782:Receptor, Bradykinin B2 / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship
chemical_list: D010455:Peptides; D043782:Receptor, Bradykinin B2; D001920:Bradykinin