Novel Dithiolane-Based Ligands Combining Sigma and NMDA Receptor Interactions as Potential Neuroprotective Agents.

Silvia Franchini,Claudia Sorbi,Rosa Maria Iacobazzi,Giulia Puja,Nunzio Denora,Annalisa Tait,Livio Brasili,Pasquale Linciano,Chiara Borsari

doi:10.1021/acsmedchemlett.0c00129

Abstract

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders. A series of novel SRs ligands were designed by combining key pharmacophoric amines (i.e., benzylpiperidine or benzylpiperazine) with new 1,3-dithiolane-based heterocycles and their bioisosters. The new compounds exhibited a low nanomolar affinity for sigma-1 and sigma-2 receptors. Five selected compounds were evaluated for their neuroprotective capacity on SH-SY5Y neuroblastoma cell line. They were able to counteract the neurotoxicity induced by rotenone, oligomycin and NMDA. Competition studies with PB212, a S1R antagonist, confirmed the involvement of S1R in neuroprotection from the oxidative stress induced by rotenone. Electrophysiological experiments performed on cortical neurons in culture highlighted the compounds ability to reduce NMDA-evoked currents, suggesting a negative allosteric modulator activity toward the NMDA receptor. Altogether these results qualify our novel dithiolane derivatives as potential agents for fighting neurodegeneration.

Highlights

Sigma receptors (SRs) are recognized as valuable targets for the treatment of neurodegenerative disorders
Oxidative cellular stress physiologically activates the sigma-1 receptor (S1R), a chaperone protein, mainly expressed in mitochondria-associated endoplasmic reticulum (ER) membranes.[5]. This receptor triggers or amplifies several cellular responses, including calcium homeostasis, reduction of glutamate release, reactive oxygen species (ROS), nitric oxide (NO), microglial activity, and upregulation of antiapoptotic genes (i.e., Bcl-2), leading to neuroprotective effects.[6−8] S1R agonists have demonstrated neuroprotective properties using in vivo models of Alzheimer’s disease (AD).[9]
Among the numerous molecular targets that have been correlated with neurodegenerative disorders, N-methyl-D-aspartate (NMDA) receptor plays a relevant role.[11]