New conformationally homogeneous beta-turn antagonists of the human B-2 kinin receptor

We have designed and synthesized a conformationally homogeneous series of c yclic pentapeptides of the general structure c[Pro-aa(i)-D-Tic-Oic-aa(i+3)] which adopt a type-II beta -turn conformation believed important for high affinity antagonism of the bradykinin (BK) beta (2) receptor. We incorporat ed D-Tic and octahydroindole-2-carboxylic acid (Oic) residues (present in k nown active antagonists) in a cyclic pentapeptide that would place the D-aa in the i + 1 position of the beta -turn and a proline as a bridge between the C- and N-termini sides of the turn. In positions i and i + 3 alkyl, aro matic, polar or charged amino acids could be introduced without dramaticall y changing the overall structure. Ten analogues were studied using H-1 nucl ear magnetic resonance (NMR) and evaluated for their binding affinity for t he human R, receptor. The NMR data in dimethylsulfoxide (DMSO) confirmed th e structural homogeneity within. We class and, on the basis of this, one re presentative member of the series was chosen for a detailed structure deter mination using NMR data in sodium dodecylsulphate (SDS) micelles and molecu lar dynamics calculations. Despite the structural similarity, the binding a ffinity of the ten analogues was strongly influenced by the nature of the s ide-chains in positions i and i + 3, with the doubly charged analogue 49 (p K(i) = 6.2) proving best. This compound may serve as the starting point for the discovery of new non-peptide bradykinin beta (2) receptor antagonists. Copyright (C) 2001 European Peptide Society and John Wiley & Sons. Ltd.