Design and Synthesis of Potent Bradykinin Agonists Containing a Benzothiazepine Moiety

A bradykinin analogue (H-Arg-Pro-Pro-Gly-Phe-Ser-<SCP>d</SCP>-BT-Arg-OH, <BO>3</BO>) in which the Pro-Phe dipeptide was replaced by the (3S)[amino]-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (<SCP>d</SCP>-BT) moiety has been synthesized. The same modification was performed on the potent bradykinin B<INF>2</INF> receptor antagonist HOE 140 (H-<SCP>d</SCP>-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-<SCP>d</SCP>-Tic-Oic-Arg-OH), in which the -<SCP>d</SCP>-Tic-Oic- moiety was replaced by <SCP>d</SCP>-BT to yield H-<SCP>d</SCP>-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-<SCP>d</SCP>-BT-Arg-OH,<BO> 1</BO> (JMV1116). These compounds were examined in vitro for their binding affinity toward bradykinin B<INF>1</INF> and B<INF>2</INF> receptors as well as for their ability to interfere with bradykinin-induced contraction of both human umbilical vein and rat uterus. The two compounds <BO>3</BO> and <BO>1</BO> competed with [³H]bradykinin binding to the human cloned B<INF>2</INF> receptor giving K<INF>i</INF> values of 13 ± 2 and 0.7 ± 0.1 nM, respectively. Unexpectedly, both compounds were full bradykinin B<INF>2</INF> receptor agonists on the human umbilical vein (pD<INF>2</INF> = 6.60 ± 0.07 for <BO>3</BO> and 6.80 ± 0.08 for <BO>1</BO>) and rat uterus (pD<INF>2</INF> = 7.20 ± 0.09 for <BO>3</BO> and 7.50 ± 0.09 for <BO>1</BO>) preparations with the same efficacy as bradykinin. In addition <BO>1</BO> induced a concentration-dependent phosphoinositide production in CHO cells expressing the human cloned B<INF>2</INF> receptor. These data provide evidence for a bioactive conformation of bradykinin constrained at the dipeptide Pro-Phe.