Synthesis and activity of dimeric bradykinin antagonists containing diaminodicarboxylic acid bridge residues.
Enhancement of a ligand's interaction with a receptor through presenting the ligand in multimeric form is a topic of general interest. Thus dimerization of single-chain bradykinin antagonist peptides has previously been shown to be beneficial in terms of potency and duration of action. While crosslinking polypeptides at terminal positions using suitable dicarboxylic acids and diamines is comparatively straight-forward synthetically, internal dimerizations are usually achieved through oxidation or double S-alkylations of cysteine residues, resulting in metabolically unfavourable disulphide and thioether cross-links. Using suitably modified standard solid-phase peptide synthesis protocols, dimeric bradykinin antagonist peptides [H-(D-Arg)-Arg-Pro-Hyp-Gly-Phe]2-X-[(D-Phe)-Leu-Arg-OH]2 were synthesized where X corresponds to a L,L-2,7-diaminosuberic or L,L-2,9-diaminosebacic acid residue, respectively. The biological activity of these peptides was comparable to that of conventional dimeric bradykinin antagonists cross-linked through cystine or bis(succinimido)alkyl bridges.
Nycomed Pharma AS, Bioreg, Oslo, Norway.
M
M
Lange
A S
AS
Cuthbertson
R
R
Towart
P M
PM
Fischer
D000818:Animals; D065168:Bradykinin Receptor Antagonists; D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents; D003959:Diamines / Q000737:chemistry*; D003998:Dicarboxylic Acids / Q000737:chemistry*; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects
D065168:Bradykinin Receptor Antagonists; D003432:Cross-Linking Reagents; D003959:Diamines; D003998:Dicarboxylic Acids