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Synthesis, conformation and biological activity of linear and cyclic Thr 6 ‐bradykinin analogues containing N ‐benzylglycine in place of phenylalanine
Author(s) -
Biondi L.,
Filira F.,
Gobbo M.,
Scolaro B.,
Rocchi R.,
Galeazzi R.,
Orena M.,
Zeegers A.,
Piek T.
Publication year - 2001
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.358
Subject(s) - chemistry , peptide , stereochemistry , biochemistry
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 ‐benzylglycine (BzlGly) and their head‐to‐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 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 Thr 6 ‐BK causes a substantial decrease in potency. Comparable 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. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.