Modulation of Tau Protein Neurotoxic Hallmarks by Novel <i>σ</i> <sub>1</sub> R 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 (σ<sub>1</sub>R) agonists and histone deacetylase inhibitors (HDACi) to target these pathological mechanisms. Compounds 2d and 3a demonstrated high affinity for σ<sub>1</sub>R 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<sub>1</sub>R agonist profile by reversing the effect of the σ<sub>1</sub>R antagonist BD-1063. This dual-action approach, acting on both HDAC and σ<sub>1</sub>R 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.
Authors
- G Giordano (ORCID: https://orcid.org/0000-0003-0177-4430)
- Antonino N. Fallica (ORCID: https://orcid.org/0000-0003-1899-8414)
- Carla Barbaraci (ORCID: https://orcid.org/0000-0002-6155-6702)
- Antonio Di Stefano (ORCID: https://orcid.org/0000-0002-3042-2234)
- Arianna Scarlatti
- Emanuele Amata (ORCID: https://orcid.org/0000-0002-4750-3479)
- Orazio Prezzavento (ORCID: https://orcid.org/0000-0002-3521-264X)
- Lorella Pasquinucci (ORCID: https://orcid.org/0000-0003-1309-3368)
- I. Cacciatore
- Alfonsina La Mantia
- Agostino Marrazzo (ORCID: https://orcid.org/0000-0002-8728-8857)
- Giacomo Siano
- Alessandro Coco (ORCID: https://orcid.org/0000-0002-4597-1025)
- Enrique J Cobos
- Cristina Di Primio
- Antonino Cattaneo
- M. Carmen Ruiz‐Cantero
Institutions
- Istituto di Scienza e Tecnologie dell'Informazione "Alessandro Faedo" (IT)
- Scuola Normale Superiore (IT)
- Universidad de Granada (ES)
- University of Catania (IT)
- University of Chieti-Pescara (IT)
- Neuroscience Institute (IT)
- Instituto de Investigación Biosanitaria de Granada (ES)
- Institute for Bioengineering of Catalonia (ES)
- Barcelona Institute for Global Health (ES)
- National Research Council (IT)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- ChemMedChem
- Published
- 2026-03-13
- DOI
- https://doi.org/10.1002/cmdc.202500922
- Primary Topic
- Pharmacological Receptor Mechanisms and Effects
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Ministero dell'Università e della Ricerca