Comparison of three gamma-turn mimetic scaffolds incorporated into angiotensin II

Bioorg Med Chem. 2000 Sep;8(9):2375-83. doi: 10.1016/s0968-0896(00)00169-3.

Abstract

Rigidification of peptides by cyclization and iterative incorporation of well-defined secondary structure mimetics constitutes one approach to the design of non-peptidergic structures with better defined conformations. We herein present the synthesis of a potential gamma-turn mimetic scaffold, and its incorporation in the 3-5 position of angiotensin II. Two analogues of angiotensin II (Ang II) incorporating this 1,3,5-trisubstituted benzene gamma-turn scaffold were synthesized. Evaluation of the compounds in a radioligand binding assay showed that they lacked affinity to the AT1 receptor. To rationalize these results a geometrical and electrostatical comparison with Ang II analogues encompassing a bicyclic scaffold that delivered inactive pseudo peptides and an azepine scaffold producing highly active ligands was made. This analysis did not provide a clear rationale for the inactivity of the benzene gamma-turn scaffolds.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / analogs & derivatives*
  • Angiotensin II / chemistry*
  • Angiotensin II / metabolism
  • Animals
  • Benzene / chemistry
  • Binding, Competitive
  • Drug Design
  • Liver / ultrastructure
  • Membranes / chemistry
  • Models, Molecular
  • Molecular Mimicry
  • Peptides / chemical synthesis
  • Protein Structure, Secondary
  • Rats
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin / metabolism
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Peptides
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Angiotensin II
  • Benzene