New bradykinin analogues substituted in positions 7 and 8 with sterically restricted 1-aminocyclopentane-1-carboxylic acid.
A sterically constrained non-coded amino acid, 1-aminocyclopentane-1-carboxylic acid (Apc), was introduced in position 7 or 8 of the bradykinin (BK) B(2) receptor antagonist, [D-Arg(0), Hyp(3), Thi(5, 8), D-Phe(7)]BK, previously synthesized by Stewart's group. This modification is believed to reduce the flexibility of the peptides, thereby forcing the peptide backbone and side chains to adopt specific orientations. Apc substitution was combined with acylation of the N-terminus with 1-adamantaneacetic acid (Aaa). The activity of four new analogues was assayed in isolated rat uterus and in rat blood pressure tests. The results clearly demonstrated that the Apc residue inserted in position 7 led to a reduction of antagonistic properties in the rat uterus assay or even restored the agonism in the blood pressure test, whereas Apc at position 8 enhanced antagonistic potency in both the tests. In both cases, acylation of the N-terminus led to the enhancement of the antagonistic potency. On the basis of these findings, new potent and selective B(2) blockers might be designed.
Labudda
Olga
O
Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland.
Wierzba
Tomasz
T
Sobolewski
Dariusz
D
Kowalczyk
Wioleta
W
Sleszyńska
Małgorzata
M
Gawiński
Lukasz
L
Plackova
Marketa
M
Slaninová
Jirina
J
Prahl
Adam
A
D000598:Amino Acids, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D005260:Female; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2 / Q000819:agonists; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects
D000598:Amino Acids, Cyclic; D065094:Bradykinin B2 Receptor Antagonists; D003509:Cyclohexanecarboxylic Acids; D043782:Receptor, Bradykinin B2; C014966:1-aminocyclohexanecarboxylic acid; D001920:Bradykinin