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New conformationally homogeneous β‐turn antagonists of the human B 2 kinin receptor
Author(s) -
Monteagudo Edith S.,
Calvani Federico,
Catrambone Fernando,
Fincham Christopher I.,
Madami Andrea,
Meini Stefania,
Terracciano Rosa
Publication year - 2001
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/psc.321
Subject(s) - chemistry , stereochemistry , bradykinin , turn (biochemistry) , pentapeptide repeat , cyclic peptide , bradykinin receptor , peptide , receptor , nuclear magnetic resonance spectroscopy , proton nmr , biochemistry
We have designed and synthesized a conformationally homogeneous series of cyclic pentapeptides of the general structure c [Pro‐aa i ‐‐Tic‐Oic‐aa i +3 ] which adopt a type‐II′ β‐turn conformation believed important for high affinity antagonism of the bradykinin (BK) B 2 receptor. We incorporated ‐Tic and octahydroindole‐2‐carboxylic acid (Oic) residues (present in known active antagonists) in a cyclic pentapeptide that would place the ‐aa in the i +l position of the β‐turn and a proline as a bridge between the C ‐ and N ‐termini sides of the turn. In positions i and i +3 alkyl, aromatic, polar or charged amino acids could be introduced without dramatically changing the overall structure. Ten analogues were studied using 1 H nuclear magnetic resonance (NMR) and evaluated for their binding affinity for the human B 2 receptor. The NMR data in dimethylsulfoxide (DMSO) confirmed the structural homogeneity within the class and, on the basis of this, one representative member of the series was chosen for a detailed structure determination using NMR data in sodium dodecylsulphate (SDS) micelles and molecular dynamics calculations. Despite the structural similarity, the binding affinity of the ten analogues was strongly influenced by the nature of the side‐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 B 2 receptor antagonists. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.