Synthesis, Conformation and Biological Activity of Linear and Cyclic Thr6-bradykinin Analogues Containing N-benzylglycine in Place of Phenylalanine

Three linear Thr(6)-bradykinin analogues in which either one or both the two phenylalanine residues in the peptide sequence have been substituted by N-benzylglyeine (BzlGly) and their head-tu-tail cyclic analogues were synthesized and tested on an isolated rat duodenum preparation. The linear (BzlGly(5).Thr(6)BK, BzlGly(8),Thr(6)-BK and BzlGly(5.8), Thr(6)-BK) and the cyclic (cyclo BzlGly(5).Thr(6)-BK. cyclo BzlGly(8).Thr(6)-BK and cyclo BzlGly(5.8),Thr(6)-BK) peptoid-like analogues were characterized by amino acid analysis, optical rotation, analytical HPLC and MALDI-TOF mass spectroscopy. The conformational features of both tire linear and cyclic derivatives were investigated by FT-IR and CD measurements. Preliminary molecular mechanics calculations were also performed on some synthetic peptides. Pharmacological screening using the relaxation of the isolated rat duodenum preparation showed that Incorporation of N-benzylglyeine at positions 5 and/or 8 in the linear Thr(6)-BK causes a substantial decrease in potency. Comparable p incorporation in cyclo Thr(6)-BK. at position 8, or 5 and 8. resulted in nearly inactive analogues. However, cyclo BzlGly(5),Thr(6)-BK showed a potency which is of the same order of magnitude as for cyclo-BK and cyclo Thr(6)-BK.