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.

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.