Comparison of three gamma-turn mimetic scaffolds incorporated into angiotensin II.
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.
Lindman
S
S
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Centre, Uppsala University, Sweden.
Lindeberg
G
G
Nyberg
F
F
Karlén
A
A
Hallberg
A
A
D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001554:Benzene / Q000737:chemistry; D001667:Binding, Competitive; D015195:Drug Design; D008099:Liver / Q000648:ultrastructure; D008566:Membranes / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis; D017433:Protein Structure, Secondary; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000378:metabolism; D055672:Static Electricity; D013329:Structure-Activity Relationship
D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D001554:Benzene