Proton magnetic resonance studies of bradykinin antagonists

Bradykinin (BK) is a peptide hormone with sequence Arg 1 ‐Pro 2 ‐Pro 3 ‐Gly 4 ‐Phe 5 ‐Ser 6 ‐Pro 7 ‐Phe 8 ‐Arg 9 and has been implicated in a multitude of pathophysiological processes such as the ability to lower systemic blood pressure and stimulate pain. BK analogues having bulky, β‐branched D ‐aliphatic residues at position 7 combined with bulky L ‐aliphatic residues at position 8 have now been observed to be strong antagonists. Conformational studies based on two‐dimensional nmr experiments in methanol/water (80/20 v/v) were carried out on several such active antagonists in a polar solvent. Included in this study were the very active antagonists, [ D ‐Arg 0 , Hyp 3 , Thi 5 , D ‐Cpg 7 , Cpg 8 ]‐BK [Cpg: α‐cyclo‐pentyl‐glycine; Hyp: trans ‐4‐hydroxy‐ L ‐proline; Thi: β‐(2‐thienyl)‐ L ‐alanine] ( I ), [ D ‐Arg 0 , Hyp 3 , D ‐Cpg 7 , Cpg 8 ] ‐BK ( II ), as well as its variant with D ‐Cpg 7 replaced by Cpg 7 , namely [ D ‐Arg 0 , Hyp 3 , Cpg 7 , Cpg 8 ]‐BK ( III ). A turn‐like structure, which coexists with the extended conformation, was observed between residues 2 and 5 for the most active antagonists I and II , in direct correlation with the peptide activities. No turn‐like structure was found for residues 6–9. In peptide III , a turn‐like structure was not identified. The existence of a turn at the C‐terminal end of bradykinin and its analogues has been predicted by empirical calculations and supported by nmr measurements. But the present nmr study on the most active antagonists ( I , II ) does not support this hypothesis. Instead, the data suggest that a turn‐like structure between residues 2 and 5 could be important for antagonist activity. Finally, one weak inhibitor [ D ‐Cpg 7 ]‐BK ( IV ) showed no defined secondary structure. © 1993 John Wiley & Sons, Inc.