Key result
Conformational constraint of Phe6 in angiotensin IV with e-beta-MePhe6 substitution resulted in high IRAP potency and selectivity versus AP-N or the AT1 receptor.
Conformational constraints in Angiotensin IV, specifically at Phe⁶ and Pro⁵, are important for generating selectivity and maintaining IRAP potency.
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.
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Lukaszuk et al. (2011) studied this question. Angiotensin IV analogs (beta-Me substituted or cyclic constrained) was evaluated on IRAP potency and selectivity versus AP-N or AT1 receptor. Conformational constraint of Phe6 in angiotensin IV with e-beta-MePhe6 substitution resulted in high IRAP potency and selectivity versus AP-N or the AT1 receptor.
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