SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF DIMER DERIVATIVES OF THE BRADYKININ RECEPTOR ANTAGONIST HOE-140

The synthesis and pharmacological evaluation of dimer derivatives of t he C-terminal fragments of the potent bradykinin antagonist HOE-140, l inked through their N-termini, were performed. The influence of peptid e moiety length was studied using the succinyl moiety as a linker. Our attention focused on the dimer of the C-terminal tetrapeptide of HOE- 140 (compound JMV 980), which displayed some inhibiting activity (IC50 = 247 nM) for bradykinin B-2 receptors. Unexpectedly, it was orally a ctive in inhibiting bradykinin-induced hypotension in the rat. Based o n this tetrapeptide dimer model, we synthesized pseudotetrapeptide dim er bradykinin antagonists 29 and 33, which exhibited high affinity (K- i = 76 and 61 nM, respectively) for the human cloned B-2 receptor. In addition, compound 29 inhibited bradykinin-induced contraction of the human umbilical vein giving a pK(B) value of 6.45. Compounds 29 and 33 were selective toward B-2 receptors because they did not bind to the cloned human B-1 receptor up to 10 mu M.