New analogues of bradykinin containing a conformationally restricted dipeptide fragment in their molecules.
The present paper describes the synthesis and some pharmacological properties of two new bradykinin analogues containing the ethylene-bridged dipeptide Phe-Phe in their molecules. In a further two peptides this modification was combined with acylation of the N-terminus with 1-adamantaneacetic acid. Finally, we synthesized four analogues by removing the Ser6 residue from the four peptides mentioned above. The activity of the new analogues was assayed on isolated rat uterus (RUT) and in rat blood pressure tests (BPT). The results clearly indicate that the proposed modification, alone or in combination with other changes, resulted in either a drop in antiuterotonic activity or even in conversion to an agonism. Although this tendency is not so distinct in blood pressure assays, the antagonistic potency of the new analogues is also diminished. Nevertheless, it was demonstrated that the D-amino acid in position 7 which, until recently, was considered necessary for antagonism, may be replaced, together with the amino acid occupying position 8, by a suitable, sterically restricted L,L-dipeptide unit.
Derdowska
I
I
Faculty of Chemistry, University of Gdańsk, Poland.
Prahl
A
A
Neubert
K
K
Hartrodt
B
B
Kania
A
A
Dobrowolski
D
D
Melhem
S
S
Trzeciak
H I
HI
Wierzba
T
T
Lammek
B
B
D019342:Acetic Acid / Q000737:chemistry; D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D010649:Phenylalanine / Q000737:chemistry; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D014599:Uterus / Q000187:drug effects
D000596:Amino Acids; D010455:Peptides; D010649:Phenylalanine; D000218:Adamantane; D019342:Acetic Acid; D001920:Bradykinin