New conformationally homogeneous beta-turn antagonists of the human B2 kinin receptor.
We have designed and synthesized a conformationally homogeneous series of cyclic 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) B2 receptor. We incorporated D-Tic and octahydroindole-2-carboxylic acid (Oic) residues (present in known 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, aromatic, polar or charged amino acids could be introduced without dramatically changing the overall structure. Ten analogues were studied using 1H nuclear magnetic resonance (NMR) and evaluated for their binding affinity for the human B2 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 (pKi = 6.2) proving best. This compound may serve as the starting point for the discovery of new non-peptide bradykinin B2 receptor antagonists.
Monteagudo
E S
ES
Department of Chemistry, Menarini Ricerche S.p.A., Pomezia, Roma, Italy. edith.monteagudo@tin.it
Calvani
F
F
Catrambone
F
F
Fincham
C I
CI
Madami
A
A
Meini
S
S
Terracciano
R
R
D065168:Bradykinin Receptor Antagonists; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D008956:Models, Chemical; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000737:chemistry*; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry; D013501:Surface-Active Agents / Q000494:pharmacology
D065168:Bradykinin Receptor Antagonists; D008823:Micelles; D010455:Peptides; D010456:Peptides, Cyclic; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D013501:Surface-Active Agents; D012967:Sodium Dodecyl Sulfate; D004121:Dimethyl Sulfoxide