Development of Second-Generation Phenoxyethylpiperidines as Potent Sigma-1 Receptor Agonists with Neuroprotective Potential for Alzheimer’s Disease

Sigma-1 receptor (S1R) is a "pluripotent chaperone" associated with pro-survival functions. Pieces of evidence show it as a promising therapeutic target for treating neurodegeneration. Encouraging results previously obtained with phenoxyalkylpiperidines prompted us to build a second generation of molecules using 1-[2-(4-chlorophenoxy)ethyl]-4-methylpiperidine (<b>1</b>), the most potent antiamnesic S1R ligand in vivo, as the lead-compound. Structural changes in the basic moiety and aromatic substitution were introduced, and features impacting on the S1R affinity and selectivity were clarified, also through docking studies and molecular dynamics (MD). The most promising phenoxyalkylpiperidines advanced to a phenotypic screening in <i>wfs1ab</i>^<i>KO</i> zebrafish <i>larvae</i> to assess hyperlocomotion reduction. Seven hit compounds were selected for the BiP-S1R dissociation as a measure of their agonist activity, followed by the preclinical evaluation of their activity against Alzheimer's Disease (AD) in mice. These phenoxyethylpiperidines demonstrated to potently prevent AD-like amnesia without toxicity, appearing as promising agents for further preclinical studies against neurodegeneration.