Enhanced Affinity for 3-Amino-Chromane-Derived σ₁ Receptor Ligands

Area of Science:

• Neuroscience
• Medicinal Chemistry

Background:

• The sigma-1 (σ1) receptor plays a crucial role in various physiological processes.
• It is a therapeutic target for conditions including cancer, pain, neurodegeneration, and COVID-19.

Purpose of the Study:

• To synthesize and characterize novel phenethylamine-containing 3-amino-chromane ligands.
• To evaluate their binding affinity and selectivity for the σ1 receptor.

Main Methods:

• Synthesis of 36 3-amino-chromane derivatives.
• Assay of ligand binding affinity (Ki) and selectivity against TMEM97.
• Stereochemical analysis of enantiomers.
• Cell-based assays using 661W cells.

Main Results:

• Identified 18 distinct compounds with low nM binding affinities for σ1.
• Three compounds exhibited high affinity in the 2 nM Ki range (∼8.7 pKi).
• Ligands with (3R,4R) stereochemistry showed enhanced affinity and σ1/TMEM97 selectivity.
• No significant protective effects were observed in 661W cells.

Conclusions:

• Novel 3-amino-chromane ligands demonstrate potent σ1 receptor binding.
• Specific stereochemistry is crucial for high affinity and selectivity.
• Further optimization is needed as tested ligands lacked cellular efficacy.