The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin
Articolo
Data di Pubblicazione:
2022
Citazione:
The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin / E. Bettini, S. De Martin, A. Mattarei, M. Pappagallo, S.M. Stahl, F. Bifari, C.E. Inturrisi, F. Folli, S. Traversa, P.L. Manfredi. - In: PHARMACEUTICALS. - ISSN 1424-8247. - 15:7(2022 Jul 17), pp. 882.1-882.17. [10.3390/ph15070882]
Abstract:
REL-1017 (esmethadone) is a novel N-methyl-D-aspartate receptor (NMDAR) antagonist and promising rapid antidepressant candidate. Using fluorometric imaging plate reader (FLIPR) assays, we studied the effects of quinolinic acid (QA) and gentamicin, with or without L-glutamate and REL-1017, on intracellular calcium ([Ca2+](in)) in recombinant cell lines expressing human GluN1-GluN2A, GluN1-GluN2B, GluN1-GluN2C, and GluN1-GluN2D NMDAR subtypes. There were no effects of QA on [Ca2+](in) in cells expressing GluN1-GluN2C subtypes. QA acted as a low-potency, subtype-selective, NMDAR partial agonist in GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D subtypes. REL-1017 reduced [Ca2+](in) induced by QA. In cells expressing the GluN1-GluN2D subtype, QA acted as an agonist in the presence of 0.04 mu M L-glutamate and as an antagonist in the presence of 0.2 mu M L-glutamate. REL-1017 reduced [Ca2+](in) induced by L-glutamate alone and with QA in all cell lines. In the absence of L-glutamate, gentamicin had no effect. Gentamicin was a positive modulator for GluN1-GluN2B subtypes at 10 mu M L-glutamate, for GluN1-GluN2A at 0.2 mu M L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 mu M L-glutamate. No significant changes were observed with GluN1-GluN2C NMDARs. REL-1017 reduced [Ca2+](in) induced by the addition of L-glutamate in all NMDAR cell lines in the presence or absence of gentamicin. In conclusion, REL-1017 reduced [Ca2+](in) induced by L-glutamate alone and when increased by QA and gentamicin. REL-1017 may protect cells from excessive calcium entry via NMDARs hyperactivated by endogenous and exogenous molecules.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
COVID-19; N-methyl-D-aspartate receptor; REL-1017; esmethadone; gentamicin; major depressive disorder (MDD); neuropsychiatric; quinolinic acid
Elenco autori:
E. Bettini, S. De Martin, A. Mattarei, M. Pappagallo, S.M. Stahl, F. Bifari, C.E. Inturrisi, F. Folli, S. Traversa, P.L. Manfredi
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