New cyclic bradykinin antagonists containing disulfide and lactam bridges at the N-terminal sequence.
Continuing our studies of the bioactive conformation of bradykinin (BK) antagonists, we synthesized a first series of analogues with side-chain cyclization in the N-terminal sequence. Through this conformational constraint it should be possible to gain insight into their three-dimensional structure. The cycles were proposed on the basis of existing ideas and hypotheses about the receptor bound conformation of BK and its antagonists. The reported peptides contain D-Phe at position 7 or D-Tic-Oic (D-Tetrahydroisoquinoline-3 -carboxyl-octahydroindole-2-carboxylic acid) at positions 7 and 8, respectively, and a disulfide or lactam bridge between positions 0 and 6. Syntheses, including cyclization reactions, were carried out on PAM resin. The biological activity of the lead compound [DPhe7]-BK, the linear precursors and the cyclic peptides, as estimated on isolated rat uterus, guinea pig ileum and lung strips, are in the same range. The conformational properties of the new cyclic analogues were studied through energy minimization on a model compound. The results of the calculations support the existence of low-energy structures containing a beta-turn. Therefore, such a turn in the N-terminal segment of the molecule can be proposed as an important structural feature of the bioactive conformation of BK antagonists.
Seyfarth
L
L
Institute For Biochemistry and Biophysics, Friedrich Schiller University, Jena, Germany.
Pineda de Castro
L F
LF
Liepina
I
I
Paegelow
I
I
Liebmann
C
C
Reissmann
S
S
D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003198:Computer Simulation; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D007769:Lactams / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011498:Protein Precursors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects*
D004220:Disulfides; D007769:Lactams; D010456:Peptides, Cyclic; D011498:Protein Precursors; D001920:Bradykinin