Synthesis, conformation and biological activity of linear and cyclic Thr⁶‐bradykinin analogues containing N‐benzylglycine in place of phenylalanine

Abstract

Three linear Thr6-bradykinin analogues in which either one or both the two phenylalanine residues in the peptide sequence have been substituted by N-benzylglycine (BzlGly) and their head-to-tail cyclic analogues were synthesized and tested on an isolated rat duodenum preparation. The linear (BzlGly5,Thr6-BK, BzlGly8,Thr6-BK and BzlGly(5,8),Thr6-BK) and the cyclic (cyclo BzlGly5,Thr6-BK, cyclo BzlGly8,Thr6-BK and cyclo BzlGly(5,8),Thr6-BK) peptoid-like analogues were characterized by amino acid analysis, optical rotation, analytical HPLC and MALDI-TOF mass spectroscopy. The conformational features of both the 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-benzylglycine at positions 5 and/or 8 in the linear Thr6-BK causes a substantial decrease in potency. Comparable incorporation in cyclo Thr6-BK, at position 8, or 5 and 8, resulted in nearly inactive analogues. However, cyclo BzlGly5,Thr6-BK showed a potency which is of the same order of magnitude as for cyclo-BK and cyclo Thr6-BK.

Synthesis and biological activities of new side chain and backbone cyclic bradykinin analogues

“…Very recently, Biondi et al . (58) published synthesis and conformational investigations of head‐to‐tail cyclic bradykinin analogues with N ‐benzylglycine at positions 5 and 8 and Thr at position 6. They postulate a γ‐turn at the C‐terminus and discuss an optimum ring size between the head and tail of 33 atoms (57).…”

“…Since the initial investigations of Chipens et al (50,51), several head-to-tail and side chain cyclic BK analogues have been synthesized (52)(53)(54)(55)(56)(57). Very recently, Biondi et al (58) published synthesis and conformational investigations of head-to-tail cyclic bradykinin analogues with N-benzylglycine at positions 5 and 8 and Thr at position 6. They postulate a c-turn at the C-terminus and discuss an optimum ring size between the head and tail of 33 atoms (57).…”

Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

“…Active antagonists with disulfide and lactam bridges obtained via side chain cyclization were reported by us [80]. Biondi et al [81] published synthesis and conformational investigations of head to tail cyclic bradykinin analogues with Nbenzylglycine at positions 5 and 8 and Thr at position 6. The authors postulate a γ-turn at the C-terminus and discuss an optimum ring size of 33 atoms between head and tail [82].…”