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Novel AT2 R ligands were designed by substituting individual β-amino acid in the sequence of the native ligand angiotensin II (Ang II). Relative ATR selectivity and functional vascular assays (in vitro AT2 R-mediated vasorelaxation and in vivo vasodepressor action) were determined. In competition binding experiments using either AT1 R- or AT2 R- transfected HEK-293 cells, only β-Asp1 -Ang II and Ang II fully displaced [125 I]-Ang II from AT1 R. In contrast, β-substitutions at each position of Ang II exhibited AT2 R affinity, with β-Tyr4 -Ang II and β-Ile5 -Ang II exhibiting ≈1000-fold AT2 R selectivity. In mouse aortic rings, β-Tyr4 -Ang II and β-Ile5 -Ang II evoked vasorelaxation that was sensitive to blockade by the AT2 R antagonist PD123319 and the nitric oxide synthase inhibitor L-NAME. When tested with a low level of AT1 R blockade, β-Ile5 -Ang II (15 pmol/kg per minute IV for 4 hours) reduced blood pressure (BP) in conscious spontaneously hypertensive rats (β-Ile5 -Ang II plus candesartan, −24±4 mm Hg) to a greater extent than candesartan alone (−11±3 mm Hg, n=7,P &lt;0.05), an effect that was abolished by concomitant PD123319 infusion. However, in an identical experimental protocol, β-Tyr4 -Ang II had no influence on BP (n=10), and it was less stable than β-Ile5 -Ang II in plasma stability assays. Thus, this study demonstrated that a single β-amino acid substitution resulted in a compound that demonstrated both in vitro vasorelaxation and in vivo depressor activity via AT2 R. This approach to the design and synthesis of novel AT2 R-selective peptidomimetics shows great potential to provide insight into AT2 R function.

A Single β-Amino Acid Substitution to Angiotensin II Confers AT 2 Receptor Selectivity and Vascular Function

A Single β-Amino Acid Substitution to Angiotensin II Confers AT ₂ Receptor Selectivity and Vascular Function