Interaction of linear and cyclic peptide antagonists at the human B(2) kinin receptor.
The ligand receptor interactions involving the C-terminal moiety of kinin B(2) receptor antagonists Icatibant (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-Dtic-Oic-Arg-OH), MEN 11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-Dtic-Oic-Arg)c(7gamma-10alpha)) and a series of analogs modified in position 10 were investigated by radioligand-binding experiments at the wild type (WT) and at the Ser(111)Ala and Ser(111)Lys mutant human kinin B(2) receptors. Icatibant and [Lys(10)]-Icatibant maintained the same high affinity towards the three receptors. For Icatibant-NH(2), [Ala(10)]-Icatibant, MEN 11270 and [Glu(10)]-MEN 11270, the changes in affinity at the WT and Ser(111)Lys receptors indicated that the presence of a net positive or negative charge at the C-terminal moiety of these peptides caused a decrease in affinity to the WT receptor and that Ser(111) residue is in proximity of the side chain of residue 10. The changes in affinity measured with [desArg(10)]-Icatibant and [desArg(10)]-Icatibant-NH(2), moreover, confirmed that a C-terminal charge compensation between the positive charge of Arg(10) side chain and the C-terminal free carboxylic function favours a high affinity interaction.
Pharmacology Department, Menarini Ricerche S.p.A., 50135 Florence, Italy. chimfarm@menarini-ricerche.it
Paola
P
Cucchi
Stefania
S
Meini
Laura
L
Quartara
Alessandro
A
Giolitti
Sabrina
S
Zappitelli
Luigi
L
Rotondaro
Carlo Alberto
CA
Maggi
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism*; D065168:Bradykinin Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D016297:Mutagenesis, Site-Directed; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D065168:Bradykinin Receptor Antagonists; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D001920:Bradykinin