Design and synthesis of potent bradykinin agonists containing a benzothiazepine moiety.
A bradykinin analogue (H-Arg-Pro-Pro-Gly-Phe-Ser-D-BT-Arg-OH, 3) in which the Pro-Phe dipeptide was replaced by the (3S)[amino]-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety has been synthesized. The same modification was performed on the potent bradykinin B(2) receptor antagonist HOE 140 (H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH), in which the -D-Tic-Oic- moiety was replaced by D-BT to yield H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-Arg-OH, 1 (JMV1116). These compounds were examined in vitro for their binding affinity toward bradykinin B(1) and B(2) receptors as well as for their ability to interfere with bradykinin-induced contraction of both human umbilical vein and rat uterus. The two compounds 3 and 1 competed with [(3)H]bradykinin binding to the human cloned B(2) receptor giving K(i) values of 13 +/- 2 and 0.7 +/- 0.1 nM, respectively. Unexpectedly, both compounds were full bradykinin B(2) receptor agonists on the human umbilical vein (pD(2) = 6.60 +/- 0.07 for 3 and 6.80 +/- 0.08 for 1) and rat uterus (pD(2) = 7.20 +/- 0.09 for 3 and 7.50 +/- 0.09 for 1) preparations with the same efficacy as bradykinin. In addition 1 induced a concentration-dependent phosphoinositide production in CHO cells expressing the human cloned B(2) receptor. These data provide evidence for a bioactive conformation of bradykinin constrained at the dipeptide Pro-Phe.
Amblard
M
M
Laboratoire des Aminoacides Peptides et Protéines, UMR CNRS 5810, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier Cédex, France.
Daffix
I
I
Bedos
P
P
Bergé
G
G
Pruneau
D
D
Paquet
J L
JL
Luccarini
J M
JM
Bélichard
P
P
Dodey
P
P
Martinez
J
J
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D015195:Drug Design; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists* / Q000378:metabolism; D014162:Transfection; D014470:Umbilical Cord / Q000187:drug effects / Q000502:physiology; D014590:Uterine Contraction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007295:Inositol Phosphates; C122063:JMV 1116; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C122064:arginyl-prolyl-prolyl--glycyl-phenylalanyl-seryl-(3S)(amino)-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one-arginine; D001920:Bradykinin