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.