2. Academic Validation
  3. Development of Second-Generation Phenoxyethylpiperidines as Potent Sigma-1 Receptor Agonists with Neuroprotective Potential for Alzheimer's Disease

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

  • J Med Chem. 2026 Feb 26;69(4):4613-4628. doi: 10.1021/acs.jmedchem.5c03240.
Francesco Mastropasqua 1,  Anna Teresa Lisi 1,  Lucie Crouzier 2,  Gabriella Rosanna Musillo 1,  Francesca Serena Abatematteo 1,  Mauro Niso 1,  Benjamin Delprat 2,  Nicola Antonio Colabufo 1,  Vittoria Nanna 3,  Giuseppe Felice Mangiatordi 3,  Pietro Delre 3 4,  Tina Spalholz 5,  Matilde Colella 6,  Winnie Deuther-Conrad 5,  Fulvio Loiodice 1,  Tangui Maurice 2,  Antonio Laghezza 1,  Carmen Abate 1
Affiliations

Affiliations

  • 1 Department of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Via E. Orabona, 4, Bari 70125, Italy.
  • 2 MMDN, University of Montpellier, EPHE, INSERM, Montpellier, France.
  • 3 Institute of Crystallography - CNR, Via G. Amendola, 122/o, Bari 70126, Italy.
  • 4 Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, Napoli 80131, Italy.
  • 5 Department of Experimental Neurooncological Radiopharmacy, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Research Site Leipzig, Permoserstraße 15, Leipzig 04318, Germany.
  • 6 Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Via E. Orabona, 4, Bari 70125, Italy.
PMID: 41642203 DOI: 10.1021/acs.jmedchem.5c03240
Abstract

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 (1), 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 wfs1abKO zebrafish larvae 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.

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