Cytotoxicity Profiles and Neuroprotective Properties of the Novel Ifenprodil Analogues as Sigma Ligands
Daniele Zampieri,
Antonella Calabretti,
Maurizio Romano,
Sara Fortuna,
Simona Collina,
Emanuele Amata,
Maria Dichiara,
Agostino Marrazzo,
Maria Grazia Mamolo
Affiliations
Daniele Zampieri
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy
Antonella Calabretti
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy
Maurizio Romano
Department of Life Sciences, University of Trieste, Via Valerio 28, 34127 Trieste, Italy
Sara Fortuna
Italian Institute of Technology (IIT), Via E. Melen 83, 16152 Genova, Italy
Simona Collina
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Viale Taramelli 6 and 12, 27100 Pavia, Italy
Emanuele Amata
Department of Drug and Health Sciences, University of Catania, Viale Doria 6, 95125 Catania, Italy
Maria Dichiara
Department of Drug and Health Sciences, University of Catania, Viale Doria 6, 95125 Catania, Italy
Agostino Marrazzo
Department of Drug and Health Sciences, University of Catania, Viale Doria 6, 95125 Catania, Italy
Maria Grazia Mamolo
Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy
Neurodegeneration is a slow and progressive loss of neuronal cells or their function in specific regions of the brain or in the peripheral system. Among several causes responsible for the most common neurodegenerative diseases (NDDs), cholinergic/dopaminergic pathways, but also some endogenous receptors, are often involved. In this context, sigma 1 receptor (S1R) modulators can be used as neuroprotective and antiamnesic agents. Herein, we describe the identification of novel S1R ligands endowed with antioxidant properties, potentially useful as neuroprotective agents. We also computationally assessed how the most promising compounds might interact with the S1R protein’s binding sites. The in silico predicted ADME properties suggested that they could be able to cross the brain-blood-barrier (BBB), and to reach the targets. Finally, the observation that at least two novel ifenprodil analogues (5d and 5i) induce an increase of the mRNA levels of the antioxidant NRF2 and SOD1 genes in SH-SY5Y cells suggests that they might be effective agents for protecting neurons against oxidative damage.
