High affinity rigidified AT₂ receptor ligands with indane scaffolds

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• The angiotensin II type 2 receptor (AT2 receptor) is a key target in cardiovascular and neurological research.
• Selective AT2 receptor modulators are crucial for understanding receptor function and developing therapeutics.
• Structural modifications of known AT2 receptor ligands can yield novel bioactive compounds.

Purpose of the Study:

• To synthesize and characterize novel indane derivatives as potential AT2 receptor agonists and antagonists.
• To investigate the impact of stereochemistry on AT2 receptor binding affinity and functional activity.
• To identify potent AT2 receptor antagonists.

Main Methods:

• Synthesis of four enantiomer pairs of indane derivatives.
• Isolation and purification of enantiomers with >99% optical purity.
• In vitro binding assays to determine affinity (Ki) for the AT2 receptor.

Main Results:

• Synthesized indane derivatives exhibited moderate to high affinity for the AT2 receptor (Ki = 2.2-223 nM).
• Enantiomers with positive optical rotation demonstrated the highest binding affinity.
• Indane derivatives 7b and 10a were identified as highly potent AT2 receptor antagonists.
• Stereochemical alterations at the chiral center significantly modulated AT2 receptor activation, converting agonists to antagonists and vice versa.

Conclusions:

• Rigidification of the isobutyl side chain led to potent AT2 receptor modulators.
• Stereochemistry plays a critical role in the functional outcome (agonist vs. antagonist) at the AT2 receptor.
• The identified indane derivatives represent valuable tools for AT2 receptor research and potential therapeutic leads.