# Modulation of Tau Protein Neurotoxic Hallmarks by Novel σ 1R Agonists/HDAC Inhibitor Dual‐Acting Compounds

## TL;DR

Researchers developed compounds that target both sigma-1 receptors and HDACs to reduce tau protein aggregation linked to Alzheimer's disease.

## Contribution

The study introduces novel dual-acting compounds that combine sigma-1 receptor agonism and HDAC inhibition to combat tau pathology.

## Key findings

- Compounds 2d and 3a significantly reduced tau aggregation and phosphorylation at the AT8 epitope in vitro.
- Both compounds exhibited a sigma-1 receptor agonist profile in vivo by reversing the effect of BD-1063.
- Compound 2d showed better chemical stability and longer half-life compared to 3a.

## Abstract

Neurodegenerative diseases, like Alzheimer's disease (AD), are characterized by the accumulation of tau aggregates, leading to neuronal dysfunction and cognitive decline. This study explores the development of dual‐acting compounds combining sigma‐1 receptor (σ
1R) agonists and histone deacetylase inhibitors (HDACi) to target these pathological mechanisms. Compounds 2d and 3a demonstrated high affinity for σ
1R and significantly reduced tau aggregation and phosphorylation in vitro, notably at the AT8 epitope. These dual‐acting compounds destabilized tau aggregates, increased tau solubility, and showed favorable pharmacokinetic properties, with compound 2d exhibiting enhanced chemical stability and longer half‐life than 3a. In vivo, both compounds confirmed a σ
1R agonist profile by reversing the effect of the σ
1R antagonist BD‐1063. This dual‐action approach, acting on both HDAC and σ
1R pathways, holds significant potential for treating tauopathies. While further optimization and clinical evaluation are needed, these findings provide a strong foundation for the continued development of multimodal therapies for neurodegenerative diseases treatment.

This study explores the development of dual‐acting compounds combining σ
1R agonists and histone deacetylase inhibitors (HDACi). Key findings include compound 2d and 3a's high affinity for σ
1R and favorable pharmacokinetic profile and an in vivo determined σ
1R agonist profile by reversing the effect of the σ
1R antagonist BD‐1063. Compounds 2d and 3a also reduced tau aggregation and phosphorylation, notably at the AT8 epitope, and determined tau aggregates destabilization and increased tau solubility. This dual‐action approach, acting on both HDAC and σ
1R pathways, holds significant potential for treating tauopathies.© 2026 WILEY‐VCH GmbH