Title:Angiotensin Peptides as AT2 Receptor Agonists
Volume: 18
Issue: 8
Author(s): Mathias Hallberg*, Jonas Sävmarker and Anders Hallberg
Affiliation:
- Beijer Laboratory, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, BMC, Uppsala University, P.O. Box 591, SE751 24 Uppsala,Sweden
Keywords:
Angiotensin II, AT2 receptor agonist, peptide, peptidemimetic, secondary structure mimetic, bioactive conformation.
Abstract: In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported.
This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been
extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like
AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships
(SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews
discuss the role of angiotensin peptides as AT2R agonists. Furthermore, to date, there have been no reports
focusing on the medicinal chemistry perspective of peptide AT2R agonists. In the present review,
reports on linear and conformationally constrained Ang II analogues, with a focus on AT2R selective
ligands that are proven to act as agonists at the AT2 receptor are summarized. The impact of truncations
and macrocyclizations of Ang II analogues and of incorporation of scaffolds that mimic secondary structures
into Ang II related peptides is highlighted. A survey of the efforts to transform the nonselective
octapeptide Ang II to more drug-like selective AT2R agonists is presented. The relationship between the
structures of the AT2R agonists and their affinity to the AT2R is briefly discussed and common pharmacophore
elements of AT2R selective Ang II peptide analogues and selective nonpeptide AT2R agonists
are compared.
