Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein

The aggregation of Amyloid-β (Aβ) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ₁ receptor chaperone and as σ₁ agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ₁ receptor. We report that Amylovis-201 is a potent σ₁ agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ₁ receptors. Furthermore, we show for the first time that classical σ₁ receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ_25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ_25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ₁ receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.