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Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents.
Eur J Med Chem 2019; 180:268-282EJ

Abstract

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.

Authors+Show Affiliations

Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1- Via Giorgieri 1, University of Trieste, 34127, Trieste, Italy. Electronic address: dzampieri@units.it.Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1- Via Giorgieri 1, University of Trieste, 34127, Trieste, Italy. Electronic address: http://sarafortuna.eu/.Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1- Via Giorgieri 1, University of Trieste, 34127, Trieste, Italy.Department of Life Sciences, Via Valerio 28/1, University of Trieste, 34127 Trieste, Italy.Department of Life Sciences, Via Valerio 28/1, University of Trieste, 34127 Trieste, Italy.Institut für Pharmazeutische und Medizinische Chemie Westfälische Wilhelms-Universität Münster, Corrensstraβe 48, D-48149, Münster, Germany.Institut für Pharmazeutische und Medizinische Chemie Westfälische Wilhelms-Universität Münster, Corrensstraβe 48, D-48149, Münster, Germany.Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, Viale Taramelli 6 and 12, University of Pavia, 27100, Pavia, Italy.Pharmacy and Clinical Pharmacology Department Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137, Trieste, Italy.Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1- Via Giorgieri 1, University of Trieste, 34127, Trieste, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31319263

Citation

Zampieri, Daniele, et al. "Discovery of New Potent Dual Sigma receptor/GluN2b Ligands With Antioxidant Property as Neuroprotective Agents." European Journal of Medicinal Chemistry, vol. 180, 2019, pp. 268-282.
Zampieri D, Fortuna S, Calabretti A, et al. Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents. Eur J Med Chem. 2019;180:268-282.
Zampieri, D., Fortuna, S., Calabretti, A., Romano, M., Menegazzi, R., Schepmann, D., ... Mamolo, M. G. (2019). Discovery of new potent dual sigma receptor/GluN2b ligands with antioxidant property as neuroprotective agents. European Journal of Medicinal Chemistry, 180, pp. 268-282. doi:10.1016/j.ejmech.2019.07.012.
Zampieri D, et al. Discovery of New Potent Dual Sigma receptor/GluN2b Ligands With Antioxidant Property as Neuroprotective Agents. Eur J Med Chem. 2019 Jul 8;180:268-282. PubMed PMID: 31319263.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2019/07/08/ PY - 2019/05/14/received PY - 2019/06/20/revised PY - 2019/07/04/accepted PY - 2019/7/19/pubmed PY - 2019/7/19/medline PY - 2019/7/19/entrez KW - Antioxidant activity KW - GluN2B receptor KW - Molecular dynamics KW - Neuroprotective activity KW - Pan-affinity KW - Sigma receptors (σRs) SP - 268 EP - 282 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 180 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/31319263/Discovery_of_new_potent_dual_sigma_receptor/GluN2b_ligands_with_antioxidant_property_as_neuroprotective_agents L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(19)30633-6 DB - PRIME DP - Unbound Medicine ER -