2. Academic Validation
  3. Synthesis and biological evaluation of N-O heterobicyclic ring systems derived from 1,2-dihydropyridines as novel TRPA1 activators: implication in GLP-1 release and neuroprotection

Synthesis and biological evaluation of N-O heterobicyclic ring systems derived from 1,2-dihydropyridines as novel TRPA1 activators: implication in GLP-1 release and neuroprotection

  • Eur J Med Chem. 2025 Dec 15:300:118115. doi: 10.1016/j.ejmech.2025.118115.
Lucrezia Margherita Comparini 1,  Valentina Citi 1,  Gabriella Ortore 2,  Giuseppe Daniele 3,  Francesca Sardelli 1,  Giulia Galgani 1,  Giorgia Bray 1,  Carolina Filipponi 4,  Alessandro De Carli 4,  Michele Lai 4,  Michele Nardone 1,  Vincenzo Calderone 1,  Marco Falasca 5,  Mauro Pineschi 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Pisa, Via Bonanno 6/33, Pisa, Italy.
  • 2 Department of Pharmacy, University of Pisa, Via Bonanno 6/33, Pisa, Italy. Electronic address: gabriella.ortore@unipi.it.
  • 3 Department of Clinical and Experimental Medicine, Section of Metabolic Diseases and Diabetes, University of Pisa, Pisa, Italy. Electronic address: giuseppe.daniele@unipi.it.
  • 4 Retrovirus Center, Department of Translational Research and New Technologies in Medicine and Surgery, Virology Unit, Pisa University Hospital, Pisa, Italy.
  • 5 Department of Medicine and Surgery, University of Parma, Parma, Italy.
  • 6 Department of Pharmacy, University of Pisa, Via Bonanno 6/33, Pisa, Italy. Electronic address: mauro.pineschi@unipi.it.
PMID: 40911966 DOI: 10.1016/j.ejmech.2025.118115
Abstract

A set of small molecules containing an unusual sp3-rich heterobicyclic scaffold were prepared and evaluated in vitro for their ability to increase GLP-1 secretion in STC-1 cells and to protect SH-SY5Y cells from acute and chronic damage induced by glucose and methylglyoxal, respectively. The results obtained showed that some compounds, especially those containing an electron-withdrawing and/or lipophilic group at the meta position of the aryl moiety present at position 9, are effective non-covalent TRPA1 agonists. The lead compound so far individuated (compound 4b) was also prepared by asymmetric synthesis in both enantiomeric forms. Western blot and immunofluorescence analyses showed that treatment with racemic 4b restored Caspase-3 expression effectively counteracting Apoptosis activation under diabetes-mimicking conditions. These findings, together with favorable ADME properties, suggest that compound 4b can modulate neuronal apoptotic pathways in an original fashion, making it a promising affordable therapeutic candidate for neuroprotection in diabetes and neurodegenerative diseases by means of an oral administration.

Keywords

Caspase-3; Chemotypes; Docking; GLP-1; Neuroprotection; N–O heterobicycles; SH-SY5Y; TRPA1.

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