The N-Methyl-D-Aspartate Receptor Blocker REL-1017 (Esmethadone) Reduces Calcium Influx Induced by Glutamate, Quinolinic Acid, and Gentamicin

• Main Authors: Ezio Bettini (Author), Sara De Martin (Author), Andrea Mattarei (Author), Marco Pappagallo (Author), Stephen M. Stahl (Author), Francesco Bifari (Author), Charles E. Inturrisi (Author), Franco Folli (Author), Sergio Traversa (Author), Paolo L. Manfredi (Author)
• Format: Book
• Published: MDPI AG, 2022-07-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 μM L-glutamate and as an antagonist in the presence of 0.2 μM 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 μM L-glutamate, for GluN1-GluN2A at 0.2 μM L-glutamate, and for GluN1-GluN2A, GluN1-GluN2B, and GluN1-GluN2D at 0.04 μM 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.

Item Description

10.3390/ph15070882
1424-8247