A new type of bradykinin B2 receptor antagonists: bradykinin analogs with N-alkyl amino acids at position 2.
It is commonly assumed that bradykinin B2 receptor antagonists bind to a receptor site partially different from that for agonists. Thus, it is likely that there exists more than one key modification to convert bradykinin receptor agonists into antagonists. In this respect, [L-NMePhe2]-BK represents the basic structure of a new type of bradykinin B2 receptor antagonists without any replacement at position 7. This compound inhibits both in vitro bradykinin-induced contraction of the guinea pig lung strip and in vivo bradykinin-induced bronchoconstriction. Furthermore, this analog shows analgesic activity, blocks in a dose-dependent manner the bradykinin-induced Ca2+ release from macrophages and inhibits at a concentration of 10(-13) M the bradykinin-induced cytokine release from mononuclear cells. Combinations with structural modifications previously performed for other B2 receptor antagonists rather reduce than enhance the potency.
Reissmann
S
S
Institute of Biochemistry and Biophysics, University of Jena, Germany.
Greiner
G
G
Seyfarth
L
L
Paegelow
I
I
Werner
H
H
Vietinghoff
G
G
Boeckmann
S
S
Schulz
E
E
Wartner
U
U
Gera
L
L
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D012756:Sheep
D000700:Analgesics; D065168:Bradykinin Receptor Antagonists; D016207:Cytokines; D043782:Receptor, Bradykinin B2; D001920:Bradykinin; D002118:Calcium