Agonist activity at the kinin B1 receptor: Structural requirements of the central tetrapeptide

A series of analogues of desArg(9)-Lys-bradykinin (BK), Lys-Arg-X-Ac(n)c-X- Ser-Pro-Phe, in which the spacer X-Ac,c-X replaces the central tetrapeptide Pro-Pro-Gly-Phe of BK, have been synthesized and functionally characterize d at the B1 receptor. The 1-aminocycloalkane-1-carboxylic acids (Ac(6)c, Ac (7)c, Ac(8)c, Ac(9)c, Ac(12)c) were incorporated to impart conformational c onstraint and probe the importance of the hydrophobicity of the residue in the central position. The linker is varied in length (X = Gly, beta Ala, ga mma Abu) to examine the optimal distance between the biologically important residues at the N- and C-termini. The biological assays indicate that the optimal length is obtained with X = Gly, with reduced activities for the lo nger linkers. Although the size of the central cyclic amino acid does not s ignificantly alter the biological activity, the hydrophobic residue Ac(n)c which may tether the peptide in the membrane environment is required (Lys-A rg-Gly-Gly-Gly-Ser-Pro-Phe is inactive). Two of the analogues, Lys-Arg-Gly- Ac(7)c-Gly-Ser-Pro-Phe and Lys-Arg-gamma Abu-Ac(7)c-gamma Abu-Ser-Pro-Phe, have been structurally characterized in the presence of a zwitterionic lipi d environment by high-resolution NMR. Both compounds have similar structura l features, differing greatest in the distance between the termini (9 and 1 5 Angstrom for the Gly- and gamma Abu-containing analogues, respectively) T he correlation of the smaller distance with activity at the B1 receptor is in complete accord with the results from our previous examination of Lys-Ar g-NH-(CH2)(11)-CO-Ser-Pro-Phe. With the results from this series of compoun ds we are beginning to define some of the molecular descriptors important f or activity at the B1 BK receptor.