New insights into the conformational requirements of B2 bradykinin antagonism.

The conformational profiles of a selected group of a new series of small linear and cyclic penta- and hexapeptides, inspired on the C-terminal segment of second-generation bradykinin (BK) antagonists, were independently computed in order to assess the chemical and geometrical requirements necessary for BK antagonism. Specifically, four cyclic peptides: cyclo-(Gly-Thi-D-Tic-Oic-Arg), cyclo-(Gly-Ala-D-Tic-Oic-Arg), cyclo-(Abu-Ala-Ser-D-Tic-Oic-Arg), cyclo-(Abu-D-Phe-Ala-D-Tic-Oic-Arg), and a linear peptide: Thi-Ser-D-Tic-Oic-Arg were selected for the present study. The first three BK analogs are capable to antagonize kinin-induced rabbit jugular vein and rabbit aorta smooth muscle contraction, while last two show no detectable affinity for the BK B2 receptor. The conformational space of the five peptides was thoroughly explored using simulated annealing (SA) in an iterative fashion as sampling technique. The bioactive conformation was assessed by pairwise cross comparisons between each of the unique low energy conformations found for each of the different peptides studied within a 5 kcal/mol threshold in respect to the global minimum. The conformational profile of the highly potent BK antagonist HOE-140, computed in an independent study, was also used in conjunction with the bioactive form assessed in the present study, to propose a pharmacophore that includes the stereochemical requirements for B2 BK antagonism.