title: New bradykinin B(2) receptor antagonists - influence of C-terminal segment modifications on their pharmacological properties.
abstract: In the present study we describe the synthesis and some pharmacological properties of eight new analogues of bradykinin (BK). Two peptides were designed by substitution of position 7 or 8 of the known [D-Arg(0),Hyp(3),Thi(5,8),D-Phe(7)]BK antagonist (Stewart's antagonist) with L-pipecolic acid (L-Pip). The next two analogues were obtained by replacement of the d-Phe residue in position 7 of the Stewart's peptide with L-beta(2)-isoproline (L-beta(2)-iPro) or L-beta(3)-homoproline (L-beta(3)-hPro). The four analogues mentioned above were also prepared in N-acylated form with 1-adamantaneacetic acid (Aaa). Biological activity of the compounds was assessed by isolated rat uterus and rat blood pressure tests. Our results showed that L-Pip in position 7 slightly increased antagonistic potency in the blood pressure test, but it turned the analogue into an agonist in the rat uterus test. Replacement of Thi by L-Pip in position 8 also enhanced antagonism in the rat pressure test but preserved the antagonism in the rat uterus test. L-beta(2)-iPro or L-beta(3)-hPro in position 7 decreased the potencies in both tests. We also demonstrated that acylation of the N-terminus did not increase, as was claimed previously, the antagonistic potencies of the resulting peptides. The results thus support the hypothesis about the existence of different types of BK receptors in the rat uterus and blood vessels. Our studies provide new information about the structure-activity relationship of BK antagonists which may help in designing more potent BK receptor blockers.
authors.affiliation: Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland. slesza@chem.univ.gda.pl
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sleszyńska
authors.forename: Anna
authors.initials: A
authors.lastname: Kwiatkowska
authors.forename: Dariusz
authors.initials: D
authors.lastname: Sobolewski
authors.forename: Tomasz H
authors.initials: TH
authors.lastname: Wierzba
authors.forename: Joanna
authors.initials: J
authors.lastname: Katarzyńska
authors.forename: Janusz
authors.initials: J
authors.lastname: Zabrocki
authors.forename: Lenka
authors.initials: L
authors.lastname: Borovickova
authors.forename: Jirina
authors.initials: J
authors.lastname: Slaninová
authors.forename: Adam
authors.initials: A
authors.lastname: Prahl
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D005260:Female; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; C053748:B 4162; D001920:Bradykinin