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Synthesis, characterization, and conformational analysis of the D/L-Tic7 stereoisomers of the bradykinin receptor antagonist D-Arg0[Hyp3,Thi5,D-Tic7,Oic8]bradykinin
- Source :
- Biochemistry. 33(9)
- Publication Year :
- 1994
-
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' beta-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 beta-turn. These differences in low-energy conformations between the two peptides may lead to a better understanding of the molecular interaction of antagonists with the bradykinin receptor.
- Subjects :
- Models, Molecular
Stereochemistry
Protein Conformation
Molecular Sequence Data
Bradykinin
Stereoisomerism
Peptide
In Vitro Techniques
Biochemistry
Cell Line
chemistry.chemical_compound
Structure-Activity Relationship
Protein structure
Structure–activity relationship
Humans
Amino Acid Sequence
Bradykinin receptor
chemistry.chemical_classification
Receptors, Bradykinin
Antagonist
Biological activity
chemistry
Thermodynamics
Calcium
Subjects
Details
- ISSN :
- 00062960
- Volume :
- 33
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....f4bf9a65efcf9034603d7ab099f2449e