Synthesis, conformation and biological activity of linear and cyclic Thr6-bradykinin analogues containing N-benzylglycine in place of phenylalanine.
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.
Biondi
L
L
Department of Organic Chemistry, University of Padova, Biopolymer Research Centre, CNR, Italy.
Filira
F
F
Gobbo
M
M
Scolaro
B
B
Rocchi
R
R
Galeazzi
R
R
Orena
M
M
Zeegers
A
A
Piek
T
T
D001920:Bradykinin / Q000138:chemical synthesis* / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry*; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry; D034444:Peptoids; D010649:Phenylalanine / Q000737:chemistry*; D011487:Protein Conformation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013912:Threonine / Q000737:chemistry*
D010455:Peptides; D034444:Peptoids; D013912:Threonine; D010649:Phenylalanine; C423606:N-benzylglycine; D001920:Bradykinin; D005998:Glycine