Structure-Affinity relationships of novel σ₂R/TMEM97 ligands

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• The sigma 2 receptor (σ₂R), identified as transmembrane protein 97 (TMEM97), is a promising therapeutic target for neurological disorders.
• Developing selective modulators for σ₂R/TMEM97 is crucial for advancing neuroscience therapeutics.

Purpose of the Study:

• To synthesize and characterize novel benzoxazocine, benzomorphan, and methanobenzazepine ligands as potential σ₂R/TMEM97 modulators.
• To evaluate the binding affinities and selectivities of these novel ligands against σ₂R/TMEM97 and σ₁R.

Main Methods:

• Synthesis of benzoxazocine, benzomorphan, and methanobenzazepine analogs based on known norbenzomorphan scaffolds.
• Determination of binding affinities (K_i values) for σ₂R/TMEM97 and σ₁R.
• Computational docking studies to predict ligand-protein interactions.

Main Results:

• Novel analogs exhibited lower binding affinities and selectivities for σ₂R/TMEM97 compared to their norbenzomorphan counterparts.
• Ligand selectivity for σ₂R/TMEM97 over σ₁R varied, with EES-1686 derivatives showing the greatest selectivity.
• Docking studies revealed conserved electrostatic interactions (salt bridge, cation-π) between ligands and σ₂R/TMEM97 residues (Asp29, Tyr150).

Conclusions:

• The spatial orientation of pharmacophoric substituents is critical for σ₂R/TMEM97 ligand binding.
• Nitrogen atom substituents play a role in achieving selectivity for σ₂R/TMEM97 versus σ₁R.
• Understanding these structure-activity relationships can guide the design of more effective σ₂R/TMEM97-targeted therapeutics.