TY - JOUR
T1 - Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents
AU - Zampieri, Daniele
AU - Fortuna, Sara
AU - Calabretti, Antonella
AU - Romano, Maurizio
AU - Menegazzi, Renzo
AU - Schepmann, Dirk
AU - Wünsch, Bernhard
AU - Collina, Simona
AU - Zanon, Davide
AU - Mamolo, Maria Grazia
PY - 2019/10/15
Y1 - 2019/10/15
N2 - Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
AB - Among several potential applications, sigma receptors (σRs) can be used as neuroprotective agents, antiamnesic, antipsychotics and against other neurodegenerative disorders. On the other hands, antagonists of the GluN2b-subunit-containing-N-methyl-D-aspartate (NMDA) receptors are of major interest for the same purpose, being this subunit expressed in specific areas of the central nervous system and responsible for the excitatory regulation of nerve cells. Under these premises, we have synthesized and biologically tested novel hybrid derivatives obtained from the combination of phenyloxadiazolone and dihydroquinolinone scaffolds with different amine moieties, peculiar of σ2R ligands. Most of the new ligands exhibited a pan-affinity towards both σR subtypes and high affinity against GluN2b subunit. The most promising compounds belong to the dihydroquinolinone series, with the best affinity profile for the cyclohexylpiperazine derivative 28. Investigation on their biological activity showed that the new compounds were able to protect SH-SY5Y cells against oxidative stress induced by hydrogen peroxide treatment. These results proved that our dual σR/GluN2b ligands have beneficial effects in a model of neuronal oxidative stress and can represent strong candidate pharmacotherapeutic agents for minimizing oxidative stress-induced neuronal injuries.
KW - Antioxidant activity
KW - GluN2B receptor
KW - Molecular dynamics
KW - Neuroprotective activity
KW - Pan-affinity
KW - Sigma receptors (σRs)
UR - http://www.scopus.com/inward/record.url?scp=85068850477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068850477&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2019.07.012
DO - 10.1016/j.ejmech.2019.07.012
M3 - Article
C2 - 31319263
AN - SCOPUS:85068850477
VL - 180
SP - 268
EP - 282
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
ER -