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Differences in backbone structure between angiotensin II agonists and type I antagonists
J M Matsoukas1, G Agelis, A Wahhab
1Department of Chemistry, University of Patras, Greece.
Journal of Medicinal Chemistry
|November 10, 1995
Summary
New angiotensin II (ANGII) antagonists were synthesized using O-methyl-L-homoserine and delta-methoxy-L-norvaline. These compounds show potent antagonist activity, with specific structural modifications crucial for maintaining efficacy and revealing conformational differences from ANGII agonists.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Structural Biology
Background:
- Angiotensin II (ANGII) plays a critical role in cardiovascular regulation.
- Development of selective ANGII antagonists is a key therapeutic strategy.
- Understanding structure-activity relationships (SAR) and conformational properties is essential for drug design.
Purpose of the Study:
- To synthesize and characterize novel Type I ANGII antagonists.
- To investigate the impact of specific amino acid substitutions at positions 4 and 8 on antagonist activity.
- To elucidate conformational differences between ANGII agonists and Type I antagonists.
Main Methods:
- Solid-phase peptide synthesis for analog preparation.
- Reverse-phase high-performance liquid chromatography (HPLC) for purification.
- Bioassay in rat uterus to determine antagonist activity (pA2 values).
- Nuclear Overhauser Effect (NOE) spectroscopy for conformational analysis.
Main Results:
- Several novel ANGII antagonists incorporating O-methyl-L-homoserine [HSer(gamma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 were successfully synthesized and exhibited significant antagonist activities (pA2 values up to 7.6).
- Modifications at position 4 of [Sar1]ANGII analogs with delta-hydroxy-L-norvaline [Nva(delta-OH)], Nva(delta-OMe), 4'-carboxyphenylalanine [Phe(4'-COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] resulted in compounds with primarily agonist activity, indicating the importance of the tyrosine hydroxyl group.
- Conformational studies revealed the absence of the Tyr-Ile-His bend in Type I antagonists, a feature present in ANGII agonists, suggesting a distinct backbone conformation.
Conclusions:
- Replacement of Ile8 with HSer(gamma-OMe) or Nva(delta-OMe) maintains Type I antagonist activity.
- The tyrosine hydroxyl group in [Sar1]ANGII is critical, and its replacement with negatively charged or electronegative groups abolishes activity.
- A significant conformational difference, specifically the lack of the Tyr-Ile-His bend, distinguishes Type I ANGII antagonists from agonists.