Synthesis and analysis of potent, more lipophilic derivatives of the bradykinin B2 receptor antagonist peptide Hoe 140.

Bradykinin (BK) is an endogenous peptide that has been implicated in several pathological conditions, hence antagonists of its activity have therapeutic potential. The decapeptide Hoe 140 is currently one of the best BK antagonists, but interest remains in finding even more potent compounds. A library of Hoe 140 derivatives was synthesized that incorporated non-natural analogs of the cationic, naturally occurring amino acids arginine (Arg) and lysine (Lys). The modified amino acids were designed to form enhanced ionic interactions due to an increase in local hydrophobicity, which promotes desolvation of the cation in water. The potencies of the resulting peptides were determined by competitive binding assays in human A431 cells expressing the BK B2 receptor. Two of the peptides synthesized were equipotent to Hoe 140 (IC(50s) 2.99 and 3.36 nM) and the most potent was demonstrated as a functional antagonist in vitro by blocking BK-mediated phosphorylation of mitogen-activated protein (MAP) kinases. The new derivatives are more hydrophobic than Hoe 140 and thus may exhibit changes in pharmacokinetic properties when evaluated in vivo.