Four previously reported
kinin receptor peptide antagonists, including the B1 receptor-selective
peptides desArg10-HOE 140 (H-D-
Arg-Arg-Pro-
Hyp-Gly-Thi-Ser-D-
Tic-Oic-
OH) and
B-9858 (H-
Lys-Lys-
Arg-Pro-
Hyp-Gly-Igl-Ser-D-Igl-Oic-
OH), have been modified by replacement of the central tetrapeptide Pro-
Hyp-Gly-Xaa with linear alkyl spacers of variable length. The analogue of desArg10-HOE 140 containing the
11-aminoundecanoic acid as spacer,
MEN 11575 [H-D-
Arg-Arg-NH-(CH2)10-CO-Ser-D-
Tic-Oic-
OH], was found to be slightly more potent than the unmodified
peptide (pA2 = 7.1) as a
kinin B1 receptor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover,
MEN 11575 is devoid of residual agonist activity at the
kinin B1 receptor (rat ileum) and antagonist activity at the
kinin B2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by the parent
peptide desArg10-HOE 140. Therefore, despite its greatly simplified chemical structure,
MEN 11575 shows an improved pharmacological profile in terms of both potency and selectivity, and it represents a good template for the development of new
peptidomimetic kinin B1 receptor antagonists. We also report an attempt to investigate the conformational role of the flexible, linear spacer of
MEN 11575 and to design more constrained analogues, possibly locked in the bioactive conformation, using semirigid spacers based on Calpha-tetrasubstituted alpha-
amino acids of the family of 1-aminocycloalkane-1-carboxylic
acids (Acnc).