Angiotensin Peptides as AT2 Receptor Agonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• The angiotensin II type 2 receptor (AT2R) plays a role in various physiological processes.
• Nonpeptide AT2R agonists have shown therapeutic potential, with some in clinical trials.
• Limited focus exists on peptide-based AT2R agonists from a medicinal chemistry standpoint.

Purpose of the Study:

• To review the medicinal chemistry of peptide AT2R agonists.
• To summarize structure-activity relationships (SAR) of angiotensin II analogues targeting AT2R.
• To compare peptide and nonpeptide AT2R agonists.

Main Methods:

• Literature review of published reports on AT2R agonists.
• Analysis of structural modifications of angiotensin II analogues (truncations, macrocyclizations).
• Comparison of pharmacophore elements between peptide and nonpeptide AT2R ligands.

Main Results:

• Numerous linear and conformationally constrained angiotensin II analogues acting as AT2R agonists have been reported.
• Structural modifications, including macrocyclization and scaffold incorporation, enhance AT2R selectivity and drug-like properties.
• Common pharmacophore features exist between selective peptide and nonpeptide AT2R agonists.

Conclusions:

• Medicinal chemistry has successfully transformed the nonselective octapeptide angiotensin II into selective AT2R agonists.
• Understanding SAR is crucial for designing effective peptide-based AT2R therapeutics.
• Further research into peptide AT2R agonists holds promise for novel anti-inflammatory and antifibrotic treatments.