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 t he Pro-Phe dipeptide was replaced by the (3S)[amino]-5-(carbonylmethyl)-2,3 -dihydro-1,5-benzothiazepin 4(5K)-one (D-BT) moiety has been synthesized. T he same modification was performed on the potent bradykinin Bz receptor ant agonist HOE 140 (H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH), in whic h 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 (JMV111G). These compounds were examined in vitr o for their binding affinity toward bradykinin B-1 and B-2 receptors as wel l as for their ability to interfere with bradykinin-induced contraction of both human umbilical vein and rat uterus. The two compounds 3 and 1 compete d with [H-3]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 com pounds were full bradykinin B-2 receptor agonists on the human umbilical ve in (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 sa me efficacy as bradykinin. In addition 1 induced a concentration-dependent phosphoinositide production in CHO cells expressing the human cloned B-2 re ceptor. These data provide evidence for a bioactive conformation of bradyki nin constrained at the dipeptide Pro-Phe.