Smooth muscle selectivity in bradykinin analogs with multiple D-amino acid substitutions.

Two novel analogs of bradykinin (BK), [DAla7]-BK and DArg-BK, exhibited a dissociation of smooth muscle activities toward higher potency on the uterus than on the ileum, in spite of increased metabolic stability to pulmonary enzymatic breakdown in the rat blood pressure assay. Analogs having a combination of the substitution of D-alanine in position 7 with a D-aromatic amino acid residue in position 6 show even greater uterus specificity. The addition of a D-arginine residue to the N-terminal greatly enhances this selectivity. Relative to BK, these poly-substituted analogs are up to 17 times as potent on the uterus as on the ileum. Still greater uterus selectivity is found among analogs in which glycine replaces the serine residue at position 6 and a D-hydrophobic amino acid residue (such as D-phenylalanine or D-p-chloro-phenylalanine) is present in position 7. These [Gly6, D-Hydrophobic7]-BK analogs are 20-40 times as potent on uterus as on ileum. [Gly6,DPhe7]-BK is the most uterus-selective analog described. In contrast, [Aib7]-BK is quite ileum-selective, having a uterus/ileum potency ratio of 0.1.