Synthesis and pharmacological evaluation of dimer derivatives of the bradykinin receptor antagonist HOE-140.
The synthesis and pharmacological evaluation of dimer derivatives of the C-terminal fragments of the potent bradykinin antagonist HOE-140, linked through their N-termini, were performed. The influence of peptide 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 B2 receptors. Unexpectedly, it was orally active in inhibiting bradykinin-induced hypotension in the rat. Based on this tetrapeptide dimer model, we synthesized pseudotetrapeptide dimer bradykinin antagonists 29 and 33, which exhibited high affinity (Ki = 76 and 61 nM, respectively) for the human cloned B2 receptor. In addition, compound 29 inhibited bradykinin-induced contraction of the human umbilical vein giving a pKB value of 6.45. Compounds 29 and 33 were selective toward B2 receptors because they did not bind to the cloned human B1 receptor up to 10 microM.
Laboratoire des Aminoacides Peptides et Protéines, UMR CNRS 5810, Université de Montpellier I, Faculté de Pharmacie, France.
I
I
Daffix
M
M
Amblard
G
G
Bergé
P
P
Dodey
D
D
Pruneau
J L
JL
Paquet
C
C
Fouchet
R M
RM
Franck
E
E
Defrêne
J M
JM
Luccarini
P
P
Bélichard
J
J
Martinez
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D019281:Dimerization; D006801:Humans; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000737:chemistry*
D000959:Antihypertensive Agents; D065168:Bradykinin Receptor Antagonists; D010455:Peptides; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D001920:Bradykinin