Modulation of Tau Protein Neurotoxic Hallmarks by Novel σ₁R Agonists/HDAC Inhibitor Dual-Acting Compounds

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 (σ₁R) agonists and histone deacetylase inhibitors (HDACi) to target these pathological mechanisms. Compounds 2d and 3a demonstrated high affinity for σ₁R 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 σ₁R agonist profile by reversing the effect of the σ₁R antagonist BD-1063. This dual-action approach, acting on both HDAC and σ₁R 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.