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

• Published in: Bioorganic & medicinal chemistry Vol. 8; no. 9; pp. 2375 - 2383
• Main Authors: Lindman, Susanna, Lindeberg, Gunnar, Nyberg, Fred, Karlén, Anders, Hallberg, Anders
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.09.2000; Elsevier Science
• Subjects: Angiotensin II - analogs & derivatives; Angiotensin II - chemistry; Angiotensin II - metabolism; Animals; Benzene - chemistry; Binding, Competitive; Chemistry; Drug Design; Exact sciences and technology; Liver - ultrastructure; Membranes - chemistry; Models, Molecular; Molecular Mimicry; Organic chemistry; Peptides; Peptides - chemical synthesis; Preparations and properties; Protein Structure, Secondary; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin - metabolism; Static Electricity; Structure-Activity Relationship; Nitrogen heterocycle; Mimetic; Peptide hormone; Lactam; Secondary structure; Modeling; Biological activity; Biological fixation; Benzylic compound; Analog; Molecular model; Peptidergic receptor; Benzenic compound; Aromatic compound; Peptide synthesis; Solid phase; Angiotensin II; Chemical synthesis; AM1 method; Seven membered ring
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00169-3

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 γ-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 γ-turn scaffold were synthesized. Evaluation of the compounds in a radioligand binding assay showed that they lacked affinity to the AT 1 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 γ-turn scaffolds.