Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists.
We recently described a potent bradykinin B(2) receptor agonist (JMV1116) obtained by replacing the D-Tic-Oic dipeptide moiety of HOE140 by a (3S)-amino-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety. This compound inhibited the specific binding of [(3)H]BK on membranes of CHO cells expressing the human cloned B(2) receptor with nanomolar affinity and contracted both isolated rat uterus and human umbilical vein. These data demonstrated that D-BT could be a good mimic of the Pro-Phe dipeptide. In the present study we characterized B(1) receptor antagonists containing the D-BT moiety. We prepared an analogue of compound JMV1116 deleting the C-terminal arginine residue. The resulting compound (1) had an affinity of 83 nM for the human cloned B(1) receptor. The most remarkable property of 1 is its ability to bind also the B(2) receptor with an affinity of 4.4 nM despite the absence of the C-terminal arginine residue. Modifications at the N-terminal part of 1 associated with the substitution of the thienylalanine residue by alpha-(2-indanyl)glycine resulted in analogues selectively binding to the B(1) receptor with an affinity in the picomolar range.
Amblard
M
M
Laboratoire des Aminoacides Peptides et Protéines, UMR5810-CNRS, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier Cédex, France.
Bedos
P
P
Olivier
C
C
Daffix
I
I
Luccarini
J M
JM
Dodey
P
P
Pruneau
D
D
Paquet
J L
JL
Martinez
J
J
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013329:Structure-Activity Relationship; D014162:Transfection; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology
D065168:Bradykinin Receptor Antagonists; C122063:JMV 1116; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D001920:Bradykinin