Garcia-Pupo_2024_Acta.Pharm.Sin.B_14_4345

The aggregation of Amyloid-beta (Abeta) 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 Abeta species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the sigma (1) receptor chaperone and as sigma (1) agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the sigma (1) receptor. We report that Amylovis-201 is a potent sigma (1) agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at sigma (1) receptors. Furthermore, we show for the first time that classical sigma (1) receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Abeta (25-35) fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Abeta (25-35) aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and sigma (1) receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.