Targeting σ₂R/TMEM97 with novel aminotetralins.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Pharmacology

Background:

• The sigma 2 receptor (σ₂R), initially linked to cancer, is now recognized for its role in central nervous system (CNS) disorders.
• Transmembrane protein 97 (TMEM97) was recently identified as the σ₂R, a poorly characterized target.

Purpose of the Study:

• To design and synthesize novel aminotetralin compounds with high affinity and selectivity for σ₂R/TMEM97.
• To identify structural features that enhance binding and selectivity against the sigma 1 receptor (σ₁R) and other CNS targets.
• To develop tool compounds for investigating σ₂R/TMEM97 function and mechanism.

Main Methods:

• Scaffold simplification strategy based on previously developed norbenzomorphans.
• Synthesis and structure-activity relationship (SAR) studies of piperazine-substituted aminotetralins.
• In vitro binding assays to determine affinity (K_i) and selectivity for σ₂R/TMEM97 versus σ₁R.
• Computational docking studies to predict ligand-receptor interactions.

Main Results:

• Identified JVW-1601 as a reference compound with high affinity (K_i = 5.5 nM) and 36-fold selectivity for σ₂R/TMEM97 over σ₁R.
• Discovered numerous analogs with K_i < 20 nM for σ₂R/TMEM97 and >20-fold selectivity.
• Optimized compound achieved K_i = 4.5 nM and 366-fold selectivity for σ₂R/TMEM97.
• JVW-1625 was crucial in confirming TMEM97 as the σ₂R.
• Docking studies revealed conserved binding interactions, including salt bridges and cation-π interactions.

Conclusions:

• Aminotetralins represent a promising class of high-affinity, selective ligands for σ₂R/TMEM97.
• These compounds serve as valuable tools for exploring the biological roles of σ₂R/TMEM97 in CNS disorders.
• The identification of TMEM97 as σ₂R opens new avenues for therapeutic development.