Synthesis, Characterization, and Conformational Analysis of the D/L-Tic7 Stereoisomers of Bradykinin Receptor Antagonist D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin

David G. Sawutz, Joseph M. Salvino, Peter R. Seoane, Brent D. Douty, Wayne T. Houck, Mark A. Bobko, Muriel S. Doleman, Roland E. Dolle, Henry R. Wolfe

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Abstract

D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin (HOE-140) is a potent (Ki= 0.11 nM) inhibitor of [3H]bradykinin binding to bradykinin B2 receptors found on human IMR-90 fetal lung fibroblasts. During the synthesis of this compound, we isolated and unambiguously identified the L-Tic7 stereoisomer (WIN 65365), which exhibits a 2000-fold lower binding affinity (Ki = 130 nM) than HOE-140 to the bradykinin receptor. A similar decrease in potency is observed for WIN 65365 inhibition of bradykinin-stimulated 45Ca2+ efflux from IMR-90 cells. Both HOE-140 and WIN 65365 appear to be competitive antagonists at the IMR-90 bradykinin receptor. This is the first documentation of bradykinin binding and functional antagonist activity by a bradykinin peptide analogue with an L amino acid replacing Pro7. In an attempt to rationalize the differences in binding affinities of HOE-140 and WIN 65365, a conformational analysis of the peptides was undertaken using annealed molecular dynamics (AMD). Conformational analysis of HOE-140 reveals a strong preference for the formation of a type II′ β-turn in the carboxy-terminal region. Analogous modeling of WIN 65365 reveals that its conformation is strikingly different from HOE-140 in that the four carboxy-terminal residues of WIN 65365 do not form a β-turn. These differences in lowenergy conformations between the two peptides may lead to a better understanding of the molecular interaction of antagonists with the bradykinin receptor.

Original languageEnglish
Pages (from-to)2373-2379
Number of pages7
JournalBiochemistry
Volume33
Issue number9
DOIs
StatePublished - Mar 1 1994

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