Structure‐activity studies on bradykinin and related peptides: agonists

1 Bradykinin, kallidin, T‐kinin, [Hyp 3 ]‐bradykinin and several analogues were prepared by solid‐phase synthesis and purified by high performance liquid chromatography. 2 The various peptides were tested for their abilities to relax the dog carotid and renal arteries, or to contract the rabbit jugular vein and aorta, in order to measure their activities on BK 2 (the first three preparations) or BK 1 (the rabbit aorta) receptors. The dog renal artery without endothelium was also used as a BK 1 receptor system. 3 T‐kinin was found to be less active than bradykinin, while the replacement of Pro 3 with Hyp favoured BK 2 receptor occupation. [Hyp 3 ,Tyr(Me) 8 ]‐BK was found to be a selective BK 2 receptor agonist. 4 Amidation or methylation of the C‐terminal carboxyl decreased activity, while extension of the N‐terminal with Sar or d ‐Arg increased affinity and selectivity for BK 1 (Sar) and affinity for BK 2 ( d ‐Arg) receptors. Acetylation of N‐terminal amide brought affinity down to 10% or less. 5 Replacement of the peptide bonds Phe 8 ‐Arg 9 to protect from kininase I and II, decreased affinities slightly, but was incompatible with additional changes at the N‐terminal or in the peptide bond Gly 4 ‐Phe 5 . 6 Substitution of C‐terminal Phe in desArg 9 ‐BK (the BK 1 receptor stimulant) with d ‐Phe increased potency and selectivity for BK 1 receptors while protecting from carboxypeptidases. Sar[ d ‐Phe 8 ]desArg 9 ‐BK was found to be a potent and selective BK 1 receptor agonist.