Bradykinin antagonists: synthesis and in vitro activity of bissuccinimidoalkane peptide dimers.
A systematic study on dimerization of the bradykinin (BK) antagonist D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Leu8-Arg9 has been performed. Several of the dimeric BK antagonists displayed remarkable activities and long durations of action. Rank order of antagonist potency as a function of dimerization position is as follows: rat uterus 6 > 5 > 0 > 2 > 1 > 3 >> 4,7,8,9; guinea pig ileum 6 > 5 > 3 > 2 > 1 > 0 >> 4,7,8,9. These results suggest that the development of BK antagonists of significant therapeutic potential may be possible using a dimerization strategy that can overcome the heretofore limiting problems of potency and in vivo duration of action.
Cheronis
J C
JC
Cortech, Inc., Denver, Colorado 80221.
Whalley
E T
ET
Blodgett
J K
JK
D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D005260:Female; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D011487:Protein Conformation; D051381:Rats; D013329:Structure-Activity Relationship; D014599:Uterus / Q000187:drug effects
D001920:Bradykinin