Correlation of secondary structures of bradykinin B1 receptor antagonists with their activity

The secondary structure of a bradykinin B(1)receptor antagonist B-10324 (F5C-Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-CpG(5)- Ser(6)-DTic(7)-CpG(8)) was determined by NMR at 800MHz. The conformational data are compared with those obtained previously for two bradykinin B(1) receptor antagonists, namely B-9858 (Lys-(1)- Lys(0)-Arg(1)-Pro(2)- Hyp(3)-Gly(4)-Igl(5)- Ser(6)-DIgl(7)-Oic(8)) and B-10148 (Lys-(1)-Lys(0)-Arg(1)- Pro(2)-Hyp(3)-Gly(4)- Igl(5)-Ser(6)-DF5F(7)- Oic(8)). The abnormal amino acids are: Hyp, trans-4- hydroxyproline; Tic, 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid; Oic, (2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid; Igl, alpha(2- indanyl)glycine; F5F, 2,3,4,5,6-pentafluorophenylalanine; CpG, alpha- cyclopentylglycine. F5C, pentafluorocinnamoyl, is the N-terminal protecting group and is not involved in the peptide secondary structure. B-10324 contains an N-terminal Pro(2)- CpG(5) distorted type II beta-turn whereas the rest of the peptide is random. A salt bridge is not observed between the carboxylate group at the C-terminal end and the Arg(1) side chain, in contrast to that previously observed for B-9858 and B- 10148. The conformations are correlated with the measured B(1) receptor antagonist activities (J.-F. Larrivée, L. Gera, S. Houle, J. Bouthillier, D. R. Bachvarov, J. M. Stewart and F. Marc au, Br. J. Pharmacol. 131, 885-892 (2000)). The importance of the N-terminal beta-turn is highlighted.