Bradykinin analogs containing the 4-amino-2-benzazepin-3-one scaffold at the C-terminus.

High affinity peptide ligands for the bradykinin (BK) B₂ subtype receptor have been shown to adopt a β-turn conformation of the C-terminal tetrapeptide (H-Arg¹-Pro²-Pro³-Gly⁴-Phe⁵-Ser⁶-Pro⁷-Phe⁸-Arg⁹-OH). We investigated the replacement of the Pro⁷-Phe⁸ dipeptide moiety in BK or the D-Tic⁷-Oic⁸ subunit in HOE140 (H-D-Arg⁰-Arg¹-Pro²-Hyp³-Gly⁴-Thi⁵-Ser⁶- D-Tic⁷-Oic⁸-Arg⁹-OH) by 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one templates (Aba). Binding studies to the human B₂ receptor showed a correlation between the affinities of the BK analogs and the propensity of the templates to adopt a β-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 B₂-expressing CHO cells up to 10 µ M 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. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]