Bradykinin analogs containing the 4-amino-2-benzazepin-3-one scaffold at the C-terminus.
High affinity peptide ligands for the bradykinin (BK) B(2) subtype receptor have been shown to adopt a beta-turn conformation of the C-terminal tetrapeptide (H-Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)-Ser(6)-Pro(7)-Phe(8)-Arg(9)-OH). We investigated the replacement of the Pro(7)-Phe(8) dipeptide moiety in BK or the D-Tic(7)-Oic(8) subunit in HOE140 (H-D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-Oic(8)-Arg(9)-OH) by 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one templates (Aba). Binding studies to the human B(2) receptor showed a correlation between the affinities of the BK analogs and the propensity of the templates to adopt a beta-turn conformation. The L-spiro-Aba-Gly containing HOE140 analog BK10 has the best affinity, which correlates with the known turn-inducing property of this template. All the compounds did not modify basal inositolphosphate (IP) output in B(2)-expressing CHO cells up to 10 microM concentration. The antagonist properties were confirmed by the guinea pig ileum smooth muscle contractility assay. The new amino-benzazepinone (Aba) substituted BK analogs were found to be surmountable antagonists.
Ballet
S
S
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
De Wachter
R
R
Van Rompaey
K
K
Tömböly
Cs
C
Feytens
D
D
Töth
G
G
Quartara
L
L
Cucchi
P
P
Meini
S
S
Tourwé
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D006801:Humans; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011487:Protein Conformation; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*
D001552:Benzazepines; D043782:Receptor, Bradykinin B2; C065679:icatibant; D001920:Bradykinin