Conformational constraints in angiotensin IV to probe the role of Tyr2, Pro5 and Phe6

The aromatic amino acids Tyr and Phe in angiotensin IV (Ang IV) were conformationally constrained by the use of β‐Me substituted analogs, or cyclic constrained analogs. None of these modifications was allowed for Tyr1, while only e‐β‐MePhe6 substitution resulted in an AngIV analog with high IRAP potency and selectivity versus AP‐N or the AT1 receptor. This indicates an important role of the orientation of the Phe6 for inducing selectivity. Pro5 replacement with 2‐aminocyclopentanecarboxylic acid maintained IRAP potency and abolished AT1 affinity. These results confirm the importance of conformational constrained amino acids to generate selectivity in bioactive peptides. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. To develop selective Ang IV analogs, conformationally constrained amino acids were introduced. No modification was allowed for Tyr1, Pro5 replacement by Acpc was tolerated, and only e‐β‐MePhe6 substitution resulted in an analog with high IRAP potency and selectivity.