Esmethadone (REL-1017) Restores NMDA Receptor 1 Subunit Expression in an In Vitro Model of Glutamatergic Excitotoxicity

Frión-Herrera, Yahima; Colognesi, Martina; Inturrisi, Charles E.; Mattarei, Andrea; Bettini, Ezio; Pappagallo, M.; Folli, Franco; Stahl, Stephen M.; Traversa, Sergio; Manfredi, Paolo L.

doi:10.1016/j.biopsych.2021.02.953

Cited by 2 publications

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“…The low affinity of REL-1017 for the NMDAR spares the block of phasic NMDAR activity, as evidenced by its lack of dissociative effects at therapeutic exposures [13,39]. Despite its low affinity, REL-1017 remains trapped in the NMDAR selectivity pore similarly to ketamine and is therefore able to reduce excessive tonic Ca 2+ currents, with downstream effects that restore synaptic proteins [40] and exert antidepressant-like effects in animal models [9], increase serum BDNF [35], and rapidly improve MDD in patients [13]. The importance of tonic blockade by uncompetitive NM-DARs in determining synaptic protein availability, synaptic enhancement, and resolution of depressive-like behavior in animal models has been anticipated by other authors [5][6][7][8].…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

et al. 2022

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Excessive Ca2+ currents via N-methyl-D-aspartate receptors (NMDARs) have been implicated in many disorders. Uncompetitive NMDAR channel blockers are an emerging class of drugs in clinical use for major depressive disorder (MDD) and other neuropsychiatric diseases. The pharmacological characterization of uncompetitive NMDAR blockers in clinical use may improve our understanding of NMDAR function in physiology and pathology. REL-1017 (esmethadone-HCl), a novel uncompetitive NMDAR channel blocker in Phase 3 trials for the treatment of MDD, was characterized together with dextromethorphan, memantine, (±)-ketamine, and MK-801 in cell lines over-expressing NMDAR subtypes using fluorometric imaging plate reader (FLIPR), automated patch-clamp, and manual patch-clamp electrophysiology. In the absence of Mg2+, NMDAR subtypes NR1-2D were most sensitive to low, sub-μM glutamate concentrations in FLIPR experiments. FLIPR Ca2+ determination demonstrated low μM affinity of REL-1017 at NMDARs with minimal subtype preference. In automated and manual patch-clamp electrophysiological experiments, REL-1017 exhibited preference for the NR1-2D NMDAR subtype in the presence of 1 mM Mg2+ and 1 μM L-glutamate. Tau off and trapping characteristics were similar for (±)-ketamine and REL-1017. Results of radioligand binding assays in rat cortical neurons correlated with the estimated affinities obtained in FLIPR assays and in automated and manual patch-clamp assays. In silico studies of NMDARs in closed and open conformation indicate that REL-1017 has a higher preference for docking and undocking the open-channel conformation compared to ketamine. In conclusion, the pharmacological characteristics of REL-1017 at NMDARs, including relatively low affinity at the NMDAR, NR1-2D subtype preference in the presence of 1 mM Mg2+, tau off and degree of trapping similar to (±)-ketamine, and preferential docking and undocking of the open NMDAR, could all be important variables for understanding the rapid-onset antidepressant effects of REL-1017 without psychotomimetic side effects.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

et al. 2022

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“…The highest dose of REL-1017 caused a significant increase of GluN1 expression in G93A SOD1 female mice. Although further studies will be needed to assess the role of NMDAR in skeletal muscles and the of REL-1017, increased NMDAR expression in specific brain areas was shown to boost neuroplasticity (50), and this putative mechanism has been suggested also as a neuroprotective effect of REL-1017 (19,51).…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice

Colognesi,

Shkodra,

Gabbia

et al. 2024

Front. Neurol.

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IntroductionThe pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.MethodsHere, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.ResultsWe found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (p < 0.01 vs. control untreated mice) and an extension of lifespan (p < 0.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (p < 0.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles.ConclusionIn conclusion, this study provides preclinical in vivo evidence supporting the clinical evaluation of REL-1017 in ALS.

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Esmethadone (REL-1017) Restores NMDA Receptor 1 Subunit Expression in an In Vitro Model of Glutamatergic Excitotoxicity

Cited by 2 publications

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Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

Pharmacological Comparative Characterization of REL-1017 (Esmethadone-HCl) and Other NMDAR Channel Blockers in Human Heterodimeric N-Methyl-D-Aspartate Receptors

Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice

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