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.
Daffix
I
I
Laboratoire des Aminoacides Peptides et Protéines, UMR CNRS 5810, Université de Montpellier I, Faculté de Pharmacie, France.
Amblard
M
M
Bergé
G
G
Dodey
P
P
Pruneau
D
D
Paquet
J L
JL
Fouchet
C
C
Franck
R M
RM
Defrêne
E
E
Luccarini
J M
JM
Bélichard
P
P
Martinez
J
J
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