Nectiv (traxoprodil) / Pfizer - LARVOL DELTA

A circuit-based, neurobehavioral assay for preclinical antidepressant profiling (Neuroscience 2024) - "Data were analyzed using a linear mixed effects model (LMM) with condition (baseline, post-treatment) and dose (vehicle, low, moderate, high) as fixed effects, focusing on 15 metrics for drug profiling and comparative analysis.We tested a panel of 12 compounds developed for Major Depressive Disorder (MDD) including Ketamine, Rapastinel, Traxoprodil, and Psilocin, all of which have “antidepressant” effects in canonical behavioral assays but vary in their clinical efficacy. This approach can enhance clinical trial predictability and reduce failure rates in antidepressant development. Our results emphasize the importance of incorporating detailed neurobehavioral investigation into preclinical research programs, paving the way for more effective and targeted MDD treatments."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

A circuit-based, neurobehavioral assay for preclinical antidepressant profiling (ECNP 2024) - "We profiled a panel of 9 compounds (each at 1-3 doses) developed for Major Depressive Disorder (MDD) including Ketamine (effective in patients), Traxoprodil (effective in Phase 2 trials, but terminated for safety reasons), Rapastinel (ineffective in patients), N,N DMT (effective in Phase 2 trials, Phase 3 pending), and Psilocin (effective in Phase 2 trials, Phase 3 ongoing), all of which have "antidepressant" effects in the canonical behavioral assay Forced Swim Test. This approach has the potential to enhance the predictability of clinical trial outcomes, reducing the high rates of failure in antidepressant development by better identifying compounds with true therapeutic potential before advancing to human trials. Our Results underscore the necessity of integrating detailed neurophysiological insights into the preclinical phase of drug development, paving the way for more effective and targeted treatments for MDD."

Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Dopamine depletion alters GluN2-subunits contribution to NMDA receptor currents in striatal projection neurons (Neuroscience 2023) - "In this study, we used MPX-004, CP101606, and NAB-14...These results suggest that dopamine loss leads to a reorganization of NMDAR subunits in i-SPNs characterized by an increased expression of GluN2B- and GluN2D-subunits, but not GluN2A-subunits and that these changes may underlie the altered activity of these neurons. Comparison of these results to findings in d-SPNs will provide further insights into the pathophysiology of striatal dysfunction in PD."

CNS Disorders • Parkinson's Disease • GRIN2A • GRIN2B

Pharmacological characterisation of the effort for reward task as a measure of motivation for reward in male mice. (PubMed, Psychopharmacology (Berl)) - "These data suggest that the EfR task is sensitive to acute dopaminergic modulation and NR2B selective antagonism in mice. However, it may lack sensitivity to non-acute phenotypic models. Further work is required to demonstrate the utility of the task in this context."

Journal • Preclinical • CNS Disorders • Psychiatry

Binding Affinity and Mechanisms of Potential Antidepressants Targeting Human NMDA Receptors. (PubMed, Molecules) - "In this study, we investigated the binding affinity and mechanisms of an FDA-approved antidepressant (S-ketamine) and seven potential antidepressants (R-ketamine, memantine, lanicemine, dextromethorphan, Ro 25-6981, ifenprodil, and traxoprodil) targeting the NMDA receptor by ligand-protein docking and molecular dynamics simulations. We further compared S-ketamine and its chiral molecule, R-ketamine, and found that R-ketamine had a stronger binding capacity to the NMDA receptor. This study provides a computational reference for the treatment of depression targeting NMDA receptors, and the proposed results will provide potential strategies for further antidepressant development and is a useful resource for the future discovery of fast-acting antidepressant candidates."

Journal • CNS Disorders • Depression • Mental Retardation • Psychiatry

Traxoprodil Produces Antidepressant-Like Behaviors in Chronic Unpredictable Mild Stress Mice through BDNF/ERK/CREB and AKT/FOXO/Bim Signaling Pathway. (PubMed, Oxid Med Cell Longev) - "Mice were randomly divided into control group, chronic unpredictable mild stress (CUMS) + vehicle group, CUMS + traxoprodil (10 mg/kg, 20 mg/kg, and 40 mg/kg) groups, and CUMS + fluoxetine (5 mg/kg) group, followed by a forced swimming test, tail suspension test, and sucrose preference test. However, at 21 days of administration, 10 and 20 mg/kg doses of traxoprodil exerted more pronounced antidepressant effects. The mechanism of traxoprodil's antidepressant effects may be closely related to the BDNF/ERK/CREB and AKT/FOXO/Bim signaling pathway."

Journal • Preclinical • AKT1 • FOXO3

Antidepressant-like effect of CP-101,606: Evidence of mTOR pathway activation. (PubMed, Mol Cell Neurosci) - "Our results demonstrate that CP-101,606 produces antidepressant effects in CUMS mice, which may be mediated by mTOR signaling cascade upregulation. Our findings suggest the possible utility of CP-101,606 as a treatment for depression."

Journal • CNS Disorders • Depression • Psychiatry • DLG4

N-methyl-D-aspartate receptor antagonists in improving cognitive deficits following traumatic brain injury: a systematic review. (PubMed, Brain Inj) - "Six NMDAR antagonists had been investigated: amantadine (n = 32), memantine (n = 4), magnesium (n = 4), traxoprodil (n = 3), selfotel (n = 2), and dextromethorphan (n = 2). Although some benefits were observed, there are still some concerns regarding the efficacy and safety of NMDAR antagonists in improving post-TBI cognitive deficits. Further research is required to examine whether (i) these agents, notably amantadine, could accelerate cognitive improvement and shorten the hospital stay, (ii) these agents affect different cognitive domains/subdomains in the same direction, (iii) an optimal therapeutic time window exists, (iv) a member of this drug class can be proved to be effective without interfering in non-excitotoxic actions of glutamate, (v) they can be more effective as part of combination therapies or in particular subgroups of patients with TBI."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Vascular Neurology

Investigational Drugs for the Treatment of Depression (Part 2): Glutamatergic, Cholinergic, Sestrin Modulators, and Other Agents. (PubMed, Front Pharmacol) - "Esketamine for treatment-resistant major depression and brexanolone for post-partum depression are two exceptions from the monoaminergic model, although their use is still limited by high costs, unique way of administration (only intravenously for brexanolone), physicians' reluctance to prescribe new drugs, and patients' reticence to use them. Glutamatergic neurotransmission is explored based on the positive results obtained by intranasal esketamine, with subanesthetic intravenous doses of ketamine, and D-cycloserine, traxoprodil, MK-0657, AXS-05, AVP-786, combinations of cycloserine and lurasidone, or dextromethorphan and quinidine, explored as therapeutic options for mono- or bipolar depression. Sestrin modulators, cholinergic receptor modulators, or onabotulinumtoxinA have also been investigated for potential antidepressant activity. In conclusion, there is hope for new treatments in uni- and bipolar depression, as it became clear, after almost 7 decades of..."

Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry

Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential. (PubMed, Food Chem Toxicol) - "Dextromethorphan (DM) abuse produces mania-like symptoms in humans. Further, ROSTA and traxoprodil also failed to enhance PKCδ depletion effect, suggesting that PKCδ is a critical target for the anti-manic potential of ROSTA or GluN2B antagonism. Our results suggest that ROSTA inhibits DM-induced manic potential by attenuating ERK/Akt activation, GluN2B/PKCδ signalings, and Nrf2-dependent system."

Journal • Bipolar Disorder • CNS Disorders • Mood Disorders

NMDARs Containing NR2B Subunit Do Not Contribute to the LTP Form of Hippocampal Plasticity: In Vivo Pharmacological Evidence in Rats. (PubMed, Int J Mol Sci) - "Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Gastrointestinal Disorder • Major Depressive Disorder • Mood Disorders • Psychiatry

Differential effects of traxoprodil and S-ketamine on quantitative EEG and auditory event-related potentials as translational biomarkers in preclinical trials in rats and mice. (PubMed, Neuropharmacology) - "In conclusion, ketamine and traxoprodil showed very different effects on diverse EEG readouts differentiating selective GluN2B antagonism from non-selective pan-NMDA-R antagonists like ketamine. These readouts are thus perfectly suited to support drug discovery efforts on NMDA-R and understanding the different functions of NMDA-R subtypes."

Journal

NMDA receptor antagonists traxoprodil and lanicemine improve hippocampal-prefrontal coupling and reward-related networks in rats. (PubMed, Psychopharmacology (Berl)) - "The antidepressant effect of NMDA antagonists appears to be associated with enhanced Hc-PFC coupling. The effects on local network properties and regional connectivity suggest that improvement of reward processing might also be important for understanding the mechanisms underlying the antidepressant effects of these drugs."

Journal • Preclinical

Blockade of GluN2B-containing NMDA receptors reduces short-term brain damage induced by early-life status epilepticus. (PubMed, Neurotoxicology) - "Fifteen minutes after pilocarpine administration, animals received i.p. injections of saline solution (0.9% NaCl; SE + SAL group), ketamine (a non-selective and noncompetitive NMDAR antagonist; 25 mg/kg; SE + KET), CI-1041 (a GluN2B-containing NMDAR antagonist; 10 mg/kg; SE + CI group) or CP-101,606 (a NMDAR antagonist with great selectivity for NMDAR composed by GluN1/GluN2B diheteromers; 10 mg/kg; SE + CP group)...However, GluN2B-containing NMDAR blockade by CI-1041 reduced neurodegeneration and Iba1/ED1 double-labeling in hippocampus and amygdala similar to the reduction observed for SE + KET group. Our results indicate that GluN2B-containing NMDAR are involved in SE-induced neurodegeneration and microglial recruitment and activation, and suggest that stopping epileptic activity is not a condition required to prevent short-term brain damage in young animals."

Journal

Mapping the central effects of (±)-ketamine and traxoprodil using pharmacological magnetic resonance imaging in awake rats. (PubMed, J Psychopharmacol) - "Traxoprodil at 5 mg/kg and 15 mg/kg produced a dose-dependent pharmacological magnetic resonance imaging signal in rat forebrain regions with both doses achieving >80% N-methyl-D-aspartate receptor subtype 2B occupancy determined by ex vivo [3H]Ro 25-6981 binding. The middle dose of traxoprodil (5 mg/kg) generated region-specific activations in medial prefrontal cortex, ventral orbital cortex, and anterior cingulate cortex whereas the high dose (15 mg/kg) produced a widespread pharmacological magnetic resonance imaging response in both cortical and subcortical brain regions which was similar to that produced by (±)-ketamine (3 mg/kg, intravenous)."

Journal • Preclinical

A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (PubMed, Drug Discov Today) - "Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217."

Journal • Review

The emergence of new antidepressants for clinical use: Agomelatine paradox versus other novel agents. (PubMed, IBRO Rep) - "...The emerging antidepressants are: selective monoamine oxidase inhibitors (MAOIs) such as bifemelane, pirlindole, toloxatone, selegiline, rasagiline and safinamide; serotonin-norepinephrine reuptake inhibitors (SNRIs) such as ansofaxine, nefopam and levomilnacipran; norepinephrine reuptake inhibitors (NRIs) such as Reboxetine, viloxazine, teniloxazine (also known as sulfoxazine or sufoxazine), and atomoxetine; Vilazodone (a serotonin 5-HT autoreceptor partial agonist with serotonin reuptake inhibition [SPARI]); Vortioxetine (a serotonin receptors antagonist with serotonin reuptake inhibition [SARI]); atypical antipsychotics such as olanzapine, quetiapine, risperidone, lurasidone, aripiprazole and brexpiprazole; N-methyl-d-aspartate (NMDA)-glutamatergic neurotransmission system blockers such as ketamine, CP-101,606 (traxoprodil), GLYX-13 (rapastinel), NRX-1074 (Apimostinel) and Riluzole...receptors antagonist [MASSA]) remains a paradoxical agent that doesn't fit..."

Clinical • Journal • Review

Glutamatergic Modulators in Depression. (PubMed, Harv Rev Psychiatry) - "These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578])."

Journal

Beyond SSRIs and SNRIs: Are Drugs That Target the NMDA Receptor, Opiate System, or Modulate Serotonin 5HT-2A Receptors on the Horizon? (ASCP 2019) - "...In the unique case of ketamine and its intranasally administered enantiomer esketamine, burgeoning evidence for acute marked antidepressant effects have drawn attention to modulation of glutamatergic transmission as a possible antidepressant strategy, particularly with respect to NMDA receptor blockade. However, few other NMDA receptor modulators have shown antidepressant efficacy in preliminary placebo-controlled trials (notably, the glycine partial agonists rapastinel and D-cycloserine). Generalizability about mechanisms to explain ketamine’s antidepressant effects remain elusive, in light of failed randomized trials of several other NMDA receptor antagonist drugs (such as riluzole, memantine, lanicemine and traxoprodil), the apparent NMDA-receptor independence of ketamine’s active metabolite norhydroxyketamine (involving, instead, AMPA receptor activation), and suspected opioid properties of ketamine (as suggested by naltrexone’s blockade of its antidepressant..."