A new class of pseudopeptide antagonists of the kinin B-1 receptor containing alkyl spacers

Four previously reported kinin receptor peptide antagonists, including the B-1 receptor-selective peptides desArg(10)-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 d esArg(10)-HOE 140 containing the 11-aminoundecanoic acid as spacer, MEN 115 75 [H-D-Arg-Arg-NH-(CH2)(10)-CO-Ser-D-Tic-Oic-OH], was found to be slightly more potent than the unmodified peptide (pA(2) = 7.1) as a kinin B-1 recep tor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover, MEN 11575 is devoid of residual agonist activity at the kinin B-1 receptor (rat ileum) and antagonist activity at the kinin B-2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by t he parent peptide desArg(10)-HOE 140. Therefore, despite its greatly simpli fied chemical structure, MEN 11575 shows an improved pharmacological profil e in terms of both potency and selectivity, and it represents a good templa te for the development of new peptidomimetic kinin B-1 receptor antagonists . We also report an attempt to investigate the conformational role of the f lexible, linear spacer of MEN 11575 and to design more constrained analogue s, possibly locked in the bioactive conformation, using semirigid spacers b ased on C-alpha-tetrasubstituted alpha-amino acids of the family of 1-amino cycloalkane-1-carboxylic acids (Ac(n)c).