New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists

Ulrika Rosenström, Christian Sköld, Bianca Plouffe, Hélène Beaudry, Gunnar Lindeberg, Milad Botros, Fred Nyberg, Gunter Wolf, Anders Karlén, Nicole Gallo-Payet*, Anders Hallberg

*Corresponding author for this work

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

New benzodiazepine-based γ-turn mimetics with one or two amino acid side chains were synthesized. The γ-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val3-Tyr4-Ile 5 or Tyr4-Ile5 peptide segments. All of the resulting pseudopeptides displayed high AT2/AT1 receptor selectivity and exhibited AT2 receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT2 receptor could position important structural elements in common areas. A previously described benzodiazepine-based γ-turn mimetic with high affinity for the AT2 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 AT2 receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44mapk, and suppress proliferation of PC12 cells.

Original languageEnglish
Pages (from-to)4009-4024
Number of pages16
JournalJournal of Medicinal Chemistry
Volume48
Issue number12
DOIs
Publication statusPublished - 16 Jun 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Rosenström, U., Sköld, C., Plouffe, B., Beaudry, H., Lindeberg, G., Botros, M., Nyberg, F., Wolf, G., Karlén, A., Gallo-Payet, N., & Hallberg, A. (2005). New selective AT2 receptor ligands encompassing a γ-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists. Journal of Medicinal Chemistry, 48(12), 4009-4024. https://doi.org/10.1021/jm0491492