New Selective AT₂Receptor Ligands Encompassing a γ-Turn Mimetic Replacing the Amino Acid Residues 4−5 of Angiotensin II Act as Agonists

Abstract

New benzodiazepine-based gamma-turn mimetics with one or two amino acid side chains were synthesized. The gamma-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val(3)-Tyr(4)-Ile(5) or Tyr(4)-Ile(5) peptide segments. All of the resulting pseudopeptides displayed high AT(2)/AT(1) receptor selectivity and exhibited AT(2) receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT(2) receptor could position important structural elements in common areas. A previously described benzodiazepine-based gamma-turn mimetic with high affinity for the AT(2) receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells.

AT2 Receptor Activities and Pathophysiological Implications

“…Major breakthrough in the investigations of AT2R activity began with the demonstration that minor substitutions to native angiotensin peptides could be a potential tool for development of new compounds to influence AT1R and AT2R activities as shown on Table 1 (58–62). In 2004, a novel AT2R agonist named Compound 21 (C21) was developed (58).…”

Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor

“…Also, the valine side chain in 1, 2 and 5 are oriented towards Ile 47 (Fig. 4) in the receptor, which could explain some of the increased affinity when a valine residue is present in the pseudopeptides, which has also been suggested before [21].…”

“…2) [18][19][20][21] was performed in the Ang II binding site of the AT 2 receptor model. The ligand-receptor complex corresponding to ligand conformation 3 in Table 1 was used as a template for building the pseudopeptides.…”

“…The binding conformation of Ang II when interacting with the AT 2 receptor has been investigated to a lesser extent, but monoand bi-cyclizations, including turn mimicking structures, in the 3-5 region of Ang II have produced analogues with retained affinity [7,[17][18][19][20][21]. An extended receptor-bound conformation of Ang II has also been suggested in the case of AT 2 binding [16].…”

“…We have previously derived models of the binding mode of several constrained pseudopeptide Ang II analogues to the AT 2 receptor using a ligand-based approach [18][19][20][21]. In the present study we aim to explore the ligand binding mode of both the pseudopeptides and the native ligand in the environment of the receptor.…”