Synthesis and <i>N</i>-Methyl-<scp>d</scp>-aspartate (NMDA) Receptor Activity of Ketamine Metabolites

Morris, Patrick J.; Moaddel, Ruin; Zanos, Panos; Moore, Curtis E.; Gould, Todd D.; Zarate, Carlos A.; Thomas, Craig J.

doi:10.1021/acs.orglett.7b02177

Cited by 69 publications

(68 citation statements)

References 23 publications

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“…Although NMDAR inhibition was long assumed to underlie ketamine’s antidepressant actions, recent evidence indicates that additional downstream mechanisms are likely to be involved. Indeed, it was recently shown that the ( 2S,6S;2R,6R )-HNK metabolite of ketamine is essential for its antidepressant actions and that ( 2R,6R )-HNK possesses robust antidepressant efficacy with low potency at the NMDAR [45, 107, 108, 353, 354]. …”

Section: Discussionmentioning

confidence: 99%

“…(2017) [105] did not observe significant antidepressant behavioral actions using a single dose of ( 2R,6R )-HNK (i.e., 10 mg/kg) following chronic social defeat stress in mice and the same group reported no effects of ( 2R,6R )-HNK in the learned helplessness paradigm in rats [106], highlighting that further studies are required to establish the effective doses of this metabolite in different animal tests predictive of antidepressant efficacy. Importantly, ( 2R,6R )-HNK does not inhibit the NMDAR at antidepressant-relevant concentrations, as was demonstrated by a lack of MK-801 displacement binding studies (Inhibitory constant: Ki > 100 μM; half maximal inhibitory concentration: IC 50 > 100 μM), lack of functional activity on NMDARs localized in stratum radiatum interneurons in rat hippocampal slices or dissociated primary cell culture [45, 107–109]. However, it does result in modest inhibition of mEPSC-NMDAR responses in mouse hippocampal cell cultures at higher concentrations [i.e., 50 μM; 108].…”

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 99%

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Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal and anti-anhedonic actions following a single administration to depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergoing pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine - pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists (i.e. GLYX-13 (rapastinel)), metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanisms Underlying Fast/rapid Onset Antidepressants Acmentioning

confidence: 99%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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“…( S )-ketamine has ~4-fold greater affinity/potency at inhibiting the NMDAR compared to its ( R )-ketamine enantiomer 13, 111–115 . Hashimoto and colleagues were the first to report superior and longer-lasting antidepressant actions of ( R )-ketamine compared with ( S )-ketamine in rodent models 116–118 .…”

Section: Nmdar Inhibition-independent Mechanismsmentioning

confidence: 99%

“…[ 3 H]-MK-801 binding displacement studies showed that the affinity of ( 2R,6R )-HNK to displace MK-801 from the NMDAR is >100 μM, and that of ( 2S,6S )-HNK is 7–20 μM 111, 112 . In addition, at 10 μM concentration, ( 2R,6R )-HNK does not functionally inhibit the NMDARs localized at stratum radiatum interneurons in hippocampal slices, compared to ~50% inhibition by ketamine at this concentration 13 .…”

Section: Nmdar Inhibition-independent Mechanismsmentioning

confidence: 99%

Mechanisms of ketamine action as an antidepressant

2018

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Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

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“…They have also been used as deuterated drugs for the optimization of metabolic and safety profiles of ketamine, leveraging the kinetic isotope effect of deuterium. Despite the existence of a number of cold synthetic approaches to ketamine and norketamine, [8][9][10][11][12][13][14][15][16] there appear to be no examples in the literature of radiolabeling at any metabolically stable positions, namely, the cyclohexyl or phenyl positions. 6,7 Ketamine itself undergoes N-demethylation in vivo as part of its biotransformation, making carbon-14 labeling at the N-methyl position unsuitable for longer duration studies.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of carbon‐14 labeled ketamine and norketamine

Chen

Gong

Salter

2018

Labelled Comp Radiopharmac

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Ketamine is a well-known general anesthetic that inhibits cerebral NMDA receptors. Norketamine is a major circulating metabolite of this drug. A nasal spray formulation of esketamine, the S enantiomer of ketamine, is under development for the management of treatment-resistant depression. To assess the pharmacokinetic properties, C-14 labeled ketamine and norketamine were prepared separately from commercially available [ C]CuCN through a five-step sequence with the C-14 label at the quaternary carbon of the cyclohexyl ring. Chiral resolution of [ C]ketamine and chiral column separation of [ C]norketamine resolved/separated the (S)-enantiomers from (R)-enantiomers.

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Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites

Cited by 69 publications

References 23 publications

Convergent Mechanisms Underlying Rapid Antidepressant Action

Convergent Mechanisms Underlying Rapid Antidepressant Action

Mechanisms of ketamine action as an antidepressant

Synthesis of carbon‐14 labeled ketamine and norketamine

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