Potent derivatives of the bradykinin B2 receptor antagonist Hoe 140 containing analogues of arginine and lysine with increased hydrophobicity

Bradykinin (BK) is an endogenous nonapeptide which serves as a local response to tissue damage and an aid to tissue repair. BK is a major pro-inflammatory agent and has been implicated in specific pathologies such as pain, edema, asthma and rhinitis, and efforts are ongoing to obtain potent and selective antagonists at the BK B2 receptor. One of the best antagonists currently available is the decapeptide Hoe 140, but interest remains in finding even more potent and longer-acting compounds. This work describes the synthesis of a series of Hoe 140 derivatives which incorporate non-natural analogues of the cationic, naturally-occurring amino acids arginine (Arg) and lysine (Lys). These analogues were designed to form enhanced ionic interactions due to an increase in local hydrophobicity which promotes desolvation of the cation in water. Physicochemical characterization confirmed the hydrophobicity, basicity, and potential for enhanced ion-pairing affinity of these amino acids. The non-natural residues were substituted for the critical Arg residues in Hoe 140 in the anticipation that the modified antagonists would show enhanced binding affinity for the B2 receptor, and thus would be more potent antagonists than the parent compound. Binding affinities of the peptides were obtained in radioligand binding studies with A431 cells expressing the B2 receptor. The data show that most of the peptides were approximately ten times less potent than Hoe 140, but two peptides, [N-o-(CH2CH2CH2)-N-o '-Arg]1-Hoe 140 (53) and [N-o Methyl-Arg]9-Hoe 140 (56), were equipotent. Although an assessment of the role of inhibition of solvation is complicated by steric factors, this study has provided compounds with potential as therapeutic agents. Previous studies have shown that increasing hydrophobicity in this fashion can result in improved in vivo potency and duration of action (Nestor et al., 1995). In preliminary experiments, 53 has been shown to be a functional antagonist of BK in vitro and further assessment in vivo is warranted. Additionally, the structure-activity relationship obtained from this study, combined with results from earlier conformational analysis, suggests that cyclic peptide derivatives of Hoe 140 may be highly potent antagonists.