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New highly potent bradykinin B2 receptor antagonists
D Regoli1, N E Rhaleb, C Tousignant
1Department of Pharmacology, Medical School, University of Sherbrooke, Quebec, Canada.
Agents and Actions
|September 1, 1991
Summary
New bradykinin B2 receptor antagonists were developed, with the most potent featuring specific amino acid substitutions. The rabbit jugular vein proved effective for evaluating these novel kinin receptor antagonists.
Area of Science:
- Pharmacology
- Medicinal Chemistry
Background:
- Bradykinin (BK) plays a role in various physiological and pathological processes.
- Selective antagonists for the B2 receptor are crucial for therapeutic applications.
Purpose of the Study:
- To synthesize and characterize novel antagonists targeting the bradykinin B2 receptor.
- To identify key structural features responsible for potent and selective B2 receptor antagonism.
Main Methods:
- Synthesis of novel peptide analogs based on bradykinin.
- In vitro bioassays using rabbit jugular vein and hamster urinary bladder preparations.
- Determination of pA2 values to quantify antagonist potency.
- Assessment of receptor selectivity against other neuropeptides.
Main Results:
- New B2 receptor antagonists exhibited pA2 values ranging from 7.51 to 8.86.
- Optimal antagonists incorporated hydroxyproline (Hyp) at position 3, D-Arg at the N-terminus, and Leu at position 8.
- The compound D-Arg[Hyp3,D-Phe7,Leu8]-BK demonstrated competitive, selective, and specific antagonism of B2 receptors.
- Modification or reorientation of the Phe8 residue in bradykinin was identified as critical for antagonism.
Conclusions:
- The rabbit jugular vein serves as a sensitive and reliable bioassay for evaluating B2 receptor antagonists.
- Specific structural modifications, particularly at the Phe8 position, are essential for developing potent and selective bradykinin B2 receptor antagonists.
- These findings contribute to the development of targeted therapies involving the kinin system.