Esmethadone-HCl (REL-1017): a promising rapid antidepressant

Abstract

This review article presents select recent studies that form the basis for the development of esmethadone into a potential new drug. Esmethadone is a promising member of the pharmacological class of uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists that have shown efficacy for major depressive disorder (MDD) and other diseases and disorders, such as Alzheimer's dementia and pseudobulbar affect. The other drugs in the novel class of NMDAR antagonists with therapeutic uses that are discussed for comparative purposes in this review are esketamine, ketamine, dextromethorphan, and memantine. We present in silico, in vitro, in vivo, and clinical data for esmethadone and other uncompetitive NMDAR antagonists that may advance our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants may advance our understanding of the neurobiology of MDD and other neuropsychiatric diseases and disorders.

Keywords: Esketamine; Esmethadone; Ketamine; Major depressive disorder; N-Methyl-D-aspartate receptor; REL-1017.

Fig. 1

Proposed mechanism of kinase involvement in uncompetitive NMDAR antagonist-mediated rapid antidepressant effects. A In the normal phenotype, physiological NR1-2D homeostatic tonic Ca²⁺ influx appropriately regulates calmodulin-dependent protein kinase III (CaMKIII) phosphorylation of eukaryotic elongation factor 2 (eEF2), which results in adequate homeostatic maintenance and availability of synaptic proteins required for action potential (AP)-mediated neural plasticity. B In the depressive phenotype, increased Ca²⁺ influx through NR1-2D channels upregulates CaMKIII-eEF2 activity, leading to the halting of synaptic protein production and availability, impairing AP-mediated neural plasticity. C Resolution of the depressive phenotype is possible through the action of uncompetitive NMDAR antagonists, such as REL-1017, which block excessive tonic Ca²⁺ currents. This blockade may restore homeostatic maintenance and availability of synaptic proteins, re-enabling physiological AP-mediated synaptic plasticity

Fig. 2

This rendering shows the interactions of uncompetitive NMDAR antagonists with the NR1-2D subtype in silico [28]. The structure of NR1-2D was obtained by electron microscopy (panel A, Protein Data Bank [PDB] code 6WHT). The black box highlights the drug-binding site. Structures of the complexes between esmethadone (light blue), arketamine (magenta), and esketamine (purple) with NR1-2D in the open conformation model (PDB code 6WHT) and the closed conformation model (PDB code 6WHS) can be seen in panels (B–D) and (E–G) [28]