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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate Jr. and Todd D. Gould
Jeffrey M. Witkin, ASSOCIATE EDITOR
Pharmacological Reviews July 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198
Panos Zanos
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Ruin Moaddel
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Patrick J. Morris
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Lace M. Riggs
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Jaclyn N. Highland
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Polymnia Georgiou
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Edna F. R. Pereira
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Edson X. Albuquerque
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Craig J. Thomas
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Carlos A. Zarate Jr.
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Todd D. Gould
Departments of Psychiatry (P.Z., L.M.R., J.N.H., P.G., T.D.G.), Pharmacology (E.F.R.P., E.X.A., T.D.G.), Anatomy and Neurobiology (T.D.G.), Epidemiology and Public Health, Division of Translational Toxicology (E.F.R.P., E.X.A.), Medicine (E.X.A.), and Program in Neuroscience (L.M.R.) and Toxicology (J.N.H.), University of Maryland School of Medicine, Baltimore, Maryland; Biomedical Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, Baltimore, Maryland (R.M.); Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Intramural Research Program, National Institutes of Health, Rockville, Maryland (P.J.M., C.J.T.); and Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland (C.A.Z.)
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Jeffrey M. Witkin
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    Major metabolic pathways. In the predominant metabolic pathway, racemic ketamine [(R,S)-KET] is initially metabolized to norketamine [(R,S)-norKET], by either CYP2B6 or CYP3A4. Subsequently, norketamine can be further metabolized to form DHNK or the HNKs. Hydroxylation of norketamine at the six position by CYP2A6 results in (2R,6S;2S,6S)-hydroxynorketamine [(2R,6R;2S,6S)-HNK]. Alternatively, CYP2B6 or CYP2A6 can hydroxylate norketamine at the four position, resulting in the 4-hydroxy isomers. In the third case, CYP2B6 can hydroxylate norketamine at the five position, resulting in (2R,5S;2S,5R)-HNK and (2R,5R;2S,5S)-HNK. (R,S)-DHNK can result either from direct dehydrogenation from norketamine via CYP2B6 or via dehydration from either diastereomer of the 5-hydroxynorketamines via a nonbiologically catalyzed process.

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    Fig. 2.

    Minor metabolic pathways. Although the majority of ketamine is metabolized via the major metabolic pathways (Fig. 1), there are several minor metabolic pathways, which provide unique, albeit low abundance, ketamine metabolites. The aryl ring of ketamine can be directly hydroxylated by flavin-containing mono-oxygenase enzymes or CYP2C9 to provide hydroxyphenyl-ketamine (hydroxyphenyl-KET). 4-Hydroxyketamine has also been observed; however, the metabolic enzymes responsible for this are currently unknown. CYP3A5 can directly hydroxylate ketamine at the six position to provide (2R,6S;2S,6R)-HK. Demethylation of (2R,6S;2S,6R)-HK with CYP3A5 provides (2R,6S;2S,6R)-HNK. CYP2A6 can also directly hydroxylate ketamine to provide (2R,6R;2S,6S)-HK, which is then transformed to (2R,6R;2S,6S)-HNK. Finally, norketamine can be hydroxylated via an unknown enzyme directly on the aryl rich to provide hydroxyphenyl-norketamine (hydroxyphenyl-norKET).

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    TABLE 1

    Relevant doses and plasma concentrations of ketamine for its clinical use and side effects in humans

    Clinical Uses and Side EffectsRoute of AdministrationKetamine DosePlasma CmaxReferences
    Clinical effects
     General anesthesiaIntravenous1.0–2 mg/kg1200–2400 ng/ml; 5–10 μMSussman (1974), Clements et al. (1982), Idvall et al. (1983), Malaquin (1984), Malinovsky et al. (1996), Dachs and Innes (1997), Yanagihara et al. (2003), Weber et al. (2004), Craven (2007), Gao et al. (2016)
    Intramuscular4–11 mg/kg
    Rectal8–10.6 mg/kg
    Oral500 mg (max)—sedation
    IntranasalFor (S)-ketamine: 3–9 mg/kgN/RWeber et al. (2004), Huge et al. (2010), Reid et al. (2011)
     AnalgesiaIntravenous0.15 mg/kg70–160 ng/ml; 0.29–0.67 μMGrant et al. (1981), Clements et al. (1982), Hirlinger and Dick (1984), Weksler et al. (1993), Eide et al. (1995), Malinovsky et al. (1996), Stubhaug et al. (1997), Lauretti et al. (1999), Azevedo et al. (2000), Flood and Krasowski (2000), Tanaka et al. (2000), Carr et al. (2004), Marchetti et al. (2015)
    Intramuscular0.5–1 mg/kg
    Intranasal2 × 10–50 mg
    Transdermal25 mg released throughout a 24-hour period
    Subcutaneous0.05–0.15 mg/kg per hour for 7 days
    Rectal10 mg/kg
    Oral2 mg/kg
    0.5 mg/kg45 ± 10 ng/ml; 0.19 ± 0.04 μMGrant et al. (1981)
     Anti-inflammationIntravenous0.15–0.25 mg/kgN/RRoytblat et al. (1998), Beilin et al. (2007), Russabrov et al. (2008)
     AntidepressantIntravenous0.5 mg/kg; 40-min infusion185 ng/ml; 0.78 μMZarate et al. (2006)
    Side effects
     DissociationIntravenous0.5 mg/kg; 40-min infusion100–250 ng/ml; 0.42–1.1 μMKrystal et al. (1994)
     Psychotomimetic effects in subjects with schizophreniaIntravenous0.3 mg/kg bolus120 ng/ml; 0.5 μMLahti et al. (2001)
    0.12 mg/kg bolus followed by a 60-min infusion of 0.65 mg/kg (total dose 0.77 mg/kg)N/RMalhotra et al. (1997)
     Cognitive and memory impairmentIntravenous40- to 120-min infusion of 0.4–0.8 mg/kgN/RMalhotra et al. (1996), Newcomer et al. (1999), Morgan et al. (2004), Mathew et al. (2010)
    0.5 mg/kg bolus350 ng/ml; 1.5 μMPfenninger et al. (2002)
    infusion over length of testing (total dose variable)N/RHarris et al. (1975), Driesen et al. (2013)
    Intramuscular0.25–0.5 mg/kg bolusN/RGhoneim et al. (1985)
     Abuse (recreational use)Intravenous1–2 mg/kgN/RSiegel (1978), Dalgarno and Shewan (1996), Jansen (2000), Arditti et al. (2002), Wolff and Winstock (2006), Bokor and Anderson (2014)
    Intramuscular50–150 mg
    Oral100–500 mg
    Intranasal30–400 mg
    • N/R, not reported.

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    TABLE 2

    Pharmacokinetic comparison for (2R,6R) and (2S,6S)-HNK in humans and rodents

    Values represent mean ± S.D.

    SpeciesDrugAdministration ParadigmTissueCmax (R,S)-KET (plasma: µM; brain: µmol/kg)Cmax (R,S)-KET (plasma: ng/ml; brain: ng/g)AUClast (R,S)-KET (plasma: h.µM; brain h. µmol/kg)AUClast (R,S)-KET (plasma: h.ng/ml; brain: h.ng/g)Cmax (2R,6R;2S,6S)-HNK (plasma: µM; brain: µmol/kg)Cmax (2R,6R;2S,6S)-HNK (plasma: ng/ml; brain: ng/g)AUClast (2R,6R;2S,6S)-HNK (plasma: h.µM; brain h. µmol/kg)AUClast (2R,6R;2S,6S)-HNK (plasma: h.ng/ml; brain: h.ng/g)References
    Humans(R,S)-KET0.5 mg/kg, 40-min i.v. infusionPlasma0.75 ± 0.23 (BD)177.23 ± 53.8 (BD)4.10 (BD)975.4 (BD)0.16 ± 0.06 (BD)37.59 ± 14.23 (BD)5.70 (BD)1366 (BD)Zarate et al. (2012a), Unpublished data
    0.86 ± 0.43 (MDD)204.13 ± 101.46 (MDD)3.67 (MDD)873.5 (MDD)0.097 ± 0.05 (MDD)23.19 ± 11.88 (MDD)4.33 (MDD)1038 (MDD)
    Rats(R,S)-KET40 mg/kg, i.v. infusionPlasma34.52 ± 2.938206 ± 69748.01 ± 21.3011,410 ± 506418.59 ± 2.814455 ± 673141.19 ± 18.533,843 ± 4432Moaddel et al. (2015b), Unpublished data
    40 mg/kg, i.p. infusionBrain137 ± 632,600 ± 1400N/AN/A30 ± 57200 ± 1200N/AN/APaul et al. (2014)
    (R)-KET20 mg/kg, i.v. infusionPlasma14.4 ± 1.68a3430 ± 400aN/AN/A1.44 ± 0.48b345 ± 115bN/AN/AMoaddel et al. (2015b)
    Brain68.84 ± 8.12a16,365 ± 1931aN/AN/A1.14 ± 0.20b274 ± 47bN/AN/A
    (S)-KET20 mg/kg, i.v. infusionPlasma11.49 ± 2.25c2732 ± 535cN/AN/A5.52 ± 0.28d1323 ± 67dN/AN/A
    Brain65.25 ± 1.91c15,512 ± 453cN/AN/A3.21 ± 0.55d769 ± 133dN/AN/A
    (R,S)-norKET20 mg/kg, i.v. infusionBrainN/AN/AN/AN/A16 ± 3bN/AN/AN/APaul et al. (2014)
    (2S,6S)-HNK20 mg/kg, i.v. infusionBrainN/AN/AN/AN/A127 ± 4dN/AN/AN/APaul et al. (2014)
    20 mg/kg, i.v. infusionPlasmaN/AN/AN/AN/A49.89 ± 1.52d11,958 ± 364d120.91 ± 25.71d28,981 ± 6162dMoaddel et al. (2015b)
    BrainN/AN/AN/AN/A127.09 ± 3.51d30,463 ± 841dN/AN/A
    20 mg/kg, oral gavagePlasmaN/AN/AN/AN/A19.66 ± 5.054713 ± 121142.22 ± 5.4810,120 ± 1313
    BrainN/AN/AN/AN/AN/AN/AN/AN/A
    Mice(R,S)-KET10 mg/kg, i.p. injectionPlasma2.36 ± 0.36561.89 ± 86.090.75177.92.81 ± 1.16674.59 ± 278.232.01480.9Zanos et al. (2016)
    Brain4.89 ± 0.851162.34 ± 202.052.07492.22.08 ± 0.21498.35 ± 50.992.49597.0Zanos et al. (2016)
    (R)-KET10 mg/kg, i.p. injectionPlasma1.40 ± 0.18a332.8 ± 42.99a0.44a104.8a2.83 ± 0.31b678.3 ± 74.54b1.85b443.0bUnpublished data
    Brain7.93 ± 1.93a1886 ± 459.6a2.48a591.9a2.47 ± 0.31b590.9 ± 74.10b2.58b618.7bZanos et al. (2016)
    (S)-KET10 mg/kg, i.p. injectionPlasma4.32 ± 1.121028 ± 266.7c1.23c293.1c2.97 ± 0.87d711.5 ± 209.4d3.62d868.1dUnpublished data
    Brain7.33 ± 2.36c1743 ± 560.6c2.03c483.1c2.21 ± 0.46d530.7 ± 111.2d4.15d995.8dZanos et al. (2016)
    (2S,6S)-HNK10 mg/kg, i.p. injectionPlasmaN/AN/AN/AN/A17.57 ± 8.72d4211 ± 2089d10.16d2435dUnpublished data
    BrainN/AN/AN/AN/A15.70 ± 8.98d3764 ± 2152d6.55d1570dZanos et al. (2016)
    (2R,6R)-HNK10 mg/kg, i.p. injectionPlasmaN/AN/AN/AN/A10.79 ± 4.76b2587 ± 1141b2.43b583.5bUnpublished data
    BrainN/AN/AN/AN/A10.66 ± 5.85b2556 ± 1402b2.19b525.3bZanos et al. (2016)
    • BD, bipolar disorder; MDD, major depressive disorder.

    • ↵a Reported values represent (R)-KET levels.

    • ↵b Reported values represent (2R,6R)-HNK levels.

    • ↵c Reported values represent (S)-KET levels.

    • ↵d Reported values represent (2S,6S)-HNK levels.

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    TABLE 3

    Molecular targets of ketamine and its metabolites

    Values represent mean ± S.E., unless otherwise indicated.

    Receptor/TargetDrugActionProposed Clinical RelevanceAffinity/ Potency (μM)MethodTissue/SystemSpeciesReference
    NMDAR(R,S)-KETAntagonistAnesthesia, antidepressant effects, amnesia, dissociative effects, abuse potential, cognitive impairmentKi = 0.49 ± 0.05RBA—[3H]MK-801 bindingCerebral cortexRatWong et al. (1986)
    Ki = 1.09RBA—[3H]MK-801 bindingBrainRatWong et al. (1988)
    Ki = 1.09RBA—[3H]MK-801 bindingBrainRatWong et al. (1988)
    Ki = 1.93RBA—[3H]TCP bindingBrainRatWong et al. (1988)
    Ki = 0.42 ± 0.03RBA—[3H]MK-801 bindingCortexHumanKornhuber et al. (1989)
    Ki = 0.18 ± 0.03RBA—[3H]MK-801 binding (no added glutamate or glycine)BrainRatReynolds and Miller (1989)
    Ki = 0.24 ± 0.10RBA—[3H]MK-801 binding (added 100 µM glutamate and 30 µM glycine)BrainRatReynolds and Miller (1989)
    Ki = 0.58 ± 0.07RBA—[3H]MK-801 bindingBrainMouseSharif et al. (1991)
    Ki = 0.76 ± 0.047RBA—[3H]MK-801 bindingBrainGuinea pigSharif et al. (1991)
    Ki = 0.48 ± 0.1RBA—[3H]MK-801 bindingBrainDogSharif et al. (1991)
    Ki = 0.71 ± 0.06RBA—[3H]MK-801 bindingCortexDogSharif et al. (1991)
    Ki = 0.6 ± 0.04RBA—[3H]MK-801 bindingSpinal cordRatSharif et al. (1991)
    Ki > 10RBA—[3H]TCP bindingRat glioma hybrid cells NG108-15RatGeorg and Friedl (1991)
    Ki = 1.19 ± 0.24RBA—[3H]MK-801 bindingCortexRatBresink et al. (1995)
    Ki = 0.20 ± 0.02RBA—[3H]MK-801 bindingBrain (synaptic membranes)RatParsons et al. (1995)
    Ki = 1.0 ± 0.5RBA—[125I]MK-801 bindingMembranes from HEK293 cells transfected with GluN1/2A receptorsRatLynch et al. (1995)
    Ki = 2.5 ± 1.2RBA—[125I]MK-801 bindingMembranes from HEK293 cells transfected with GluN1/2B receptorsRatLynch et al. (1995)
    Ki = 2.51 ± 1.90Autoradiographic binding—[3H]MK-801CerebellumRatBresink et al. (1995)
    Ki = 0.5 ± 0.15RBA—[3H]MK-801 bindingStriatumRatKapur and Seeman (2001, 2002)
    Ki = 0.92RBA—[3H]MK-801 bindingBrain membranesRatSun and Wessinger (2004)
    Ki = 3.1 ± 0.3RBA—[3H]MK-801 bindingStriatumRatSeeman et al. (2005)
    Ki = 1.35 ± 0.43RBA—[3H]MK-801 bindingCortexRatGilling et al. (2009)
    Ki = 0.67 ± 0.15RBA—[3H]MK-801 bindingCortexHumanGilling et al. (2009)
    Ki = 1.47 ± 0.68Whole-cell patch-clamp recordings—holding potential at −70 mVHEK293 cells transfected with GluN1/2A receptorsHumanGilling et al. (2009)
    Ki = 0.32 ± 0.02RBA—[3H]MK-801 bindingForebrainRatWallach et al. (2016), Kang et al. (2017)
    Ki = 0.25RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 3.91RBA—[3H]TCP bindingRat brain (minus cerebellum) synaptoneurosomal fractionsRatAllaoua and Chicheportiche (1989)
    IC50 = 5.4 ± 0.6Autoradiographic binding—[3H]MK-801Frontal cortexRatPorter and Greenamyre (1995)
    IC50 = 5.0 ± 0.6Autoradiographic binding—[3H]MK-801StriatumRatPorter and Greenamyre (1995)
    IC50 = 3.9 ± 0.5Autoradiographic binding—[3H]MK-801Entorhinal cortexRatPorter and Greenamyre (1995)
    IC50 = 6.7 ± 0.8Autoradiographic binding—[3H]MK-801Hippocampus (CA1)RatPorter and Greenamyre (1995)
    IC50 = 5.4 ± 0.6Autoradiographic binding—[3H]MK-801Dentate gyrusRatPorter and Greenamyre (1995)
    IC50 = 8.2 ± 0.6Autoradiographic binding—[3H]MK-801Cerebellar granule cell layerRatPorter and Greenamyre (1995)
    IC50 = 1.6 ± 0.01Whole-cell patch-clamp recordingsCultured superior collicular neuronesRatParsons et al. (1995)
    IC50 > 10; 100 μM induced a 63% inhibitionNMDA (10 μM)-evoked extracellular postsynaptic currentsVentral tegmental areaRatWu and Johnson (1996)
    IC50 = 1.03 ± 0.06Glutamate (0.3 μM)-evoked GluN1/2A currentstsA201 cellsRatGlasgow et al. (2017)
    IC50 = 0.89 ± 0.07Glutamate (1 mM)-evoked GluN1/2A currentstsA201 cellsRatGlasgow et al. (2017)
    IC50 = 0.59 ± 0.03Glutamate (0.3 μM)-evoked GluN1/2B currentstsA201 cellsRatGlasgow et al. (2017)
    IC50 = 0.43 ± 0.04Glutamate (1 mM)-evoked GluN1/2B currentstsA201 cellsRatGlasgow et al. (2017)
    IC50 = 0.43 ± 0.10Whole-cell patch-clamp recordingsHippocampusRatParsons et al. (1996)
    IC50 = 0.92 ± 0.21Whole-cell patch-clamp recordingsStriatumRatParsons et al. (1996)
    2 mM Mg2+Two-microelectrode recordingRat receptors expressed in Xenopus oocytesRatDravid et al. (2007)
    GluN1/2A: IC50 = 3.31
    GluN1/2B: IC50 = 0.93
    GluN1/2C: IC50 = 1.65
    GluN1/2D: IC50 = 2.42
    IC50 = 7.97FLIPR calcium influx assayHEK293 cellsHumanGilling et al. (2009)
    IC50 = 0.71 ± 0.03Whole-cell patch-clamp recordings—holding potential at −70 mVHumanGilling et al. (2009)
    IC50 = 6.05 ± 0.66Whole-cell patch-clamp recordings—holding potential at 0 mVHEK293 cells transfected with GluN1/2A receptorsHumanGilling et al. (2009)
    Mg2+ freeWhole-cell recordingsRat receptor expressed in HEK293 cellsRatKotermanski and Johnson (2009)
    GluN1/2A: IC50 = 0.33 ± 0.01; GluN1/2B: IC50 = 0.31 ± 0.02; GluN1/2C: IC50 = 0.51 ± 0.01; GluN1/2D: IC50 = 0.83 ± 0.02
    1 mM Mg2+Whole-cell recordingsRat receptor expressed in HEK293 cellsRatKotermanski and Johnson (2009)
    GluN1/2A: IC50 = 5.35 ± 0.34; GluN1/2B: IC50 = 5.08 ± 0.02; GluN1/2C: IC50 = 1.18 ± 0.04; GluN1/2D: IC50 = 2.95 ± 0.02
    IC50 = 10Extracellular recordings (EPSPs)Hippocampus (CA1)RatIzumi and Zorumski (2014)
    IC50 = 0.40Whole-cell patch-clamp recordingsHippocampal neuron cultureRatEmnett et al. (2016)
    IC50 = 0.51 ± 0.04RBA—[3H]MK-801 bindingForebrainRatWallach et al. (2016), Kang et al. (2017)
    IC50 = 0.35RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (S)-KETAntagonistAnesthesia, antidepressant effects, dissociative effects, cognitive impairmentKi = 0.30 ± 0.013RBA—[3H]MK-801 bindingCortexRatEbert et al. (1997)
    Ki = 0.69 ± 0.09RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 0.42 ± 0.04RBA—[3H]MK-801 bindingCortexPigBonifazi et al. (2015)
    Ki = 0.44 ± 0.10RBA—[3H]MK-801 bindingCortexPigTemme et al. (2018)
    IC50 = 1.6–1.9RBA—[3H]MK-801 bindingHippocampus (two brain samples only)HumanOye et al. (1992)
    IC50 = 1.5–2.8RBA—[3H]MK-801 bindingFrontal cortex (two brain samples only)HumanOye et al. (1992)
    IC50 = 1.6–2.1RBA—[3H]MK-801 bindingOccibital cortex (two brain samples only)HumanOye et al. (1992)
    IC50 = 0.80Whole-cell patch-clamp recordingsHippocampusRatZeilhofer et al. (1992)
    IC50 = 0.9 ± 1.4NMDA (μM)-evoked currentsCortexRatEbert et al. (1997)
    2 mM Mg2+Two-microelectrode recordingRat receptors expressed in Xenopus ooctyesRatDravid et al. (2007)
    GluN1/2A: IC50 = 16.10
    GluN1/2B: IC50 = 1.55
    GluN1/2C: IC50 = 1.11
    GluN1/2D: IC50 = 1.50
    (R)-KETAntagonistAnesthesia, antidepressant effectsKi = 1.40 ± 0.1RBA—[3H]MK-801 bindingCortexRatEbert et al. (1997)
    Ki = 2.57 ± 0.28RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 1.79 ± 0.31RBA—[3H]MK-801 bindingCortexPigTemme et al. (2018)
    IC50 = 7.2–10RBA—[3H]MK-801 bindingHippocampus (two brain samples only)HumanOye et al. (1992)
    IC50 = 8.2–13.7RBA—[3H]MK-801 bindingFrontal cortex (two brain samples only)HumanOye et al. (1992)
    IC50 = 10.9–11.4RBA—[3H]MK-801 bindingOccibital cortex (two brain samples only)HumanOye et al. (1992)
    IC50 = 1.53Whole-cell patch-clamp recordingsHippocampusRatZeilhofer et al. (1992)
    IC50 = 3.0 ± 1.4NMDA (μM)-evoked currentsCortexRatEbert et al. (1997)
    (R,S)-norKETAntagonistAnesthesiaKi = 3.60 ± 0.49RBA—[3H]MK-801 bindingCortexRatEbert et al. (1997)
    2 mM Mg2+Two-microelectrode recordingRat receptors expressed in Xenopus ooctyesRatDravid et al. (2007)
    GluN1/2A: IC50 = 50.90
    GluN1/2B: IC50 = 8.74
    GluN1/2C: IC50 = 5.6
    GluN1/2D: IC50 = 7.5
    IC50 = 2.00Whole-cell recordingsHippocampal neuron cultureRatEmnett et al. (2016)
    (S)-norKETAntagonistKi = 1.7 ± 0.050RBA—[3H]MK-801 bindingCortexRatEbert et al. (1997)
    Ki = 2.25 ± 0.22RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 0.87RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 3.0 ± 0.8NMDA (μM)-evoked currentsCortexRatEbert et al. (1997)
    IC50 = 1.23RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (R)-norKETAntagonistKi = 13 ± 1.8RBA—[3H]MK-801 bindingCortexRatEbert et al. (1997)
    Ki = 26.46RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 0.60RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 39.0 ± 1.4NMDA (μM)-evoked currentsCortexRatEbert et al. (1997)
    IC50 = 0.85RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (S)-DHNKAntagonistN/AKi = 38.95RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 29.7RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 42.0RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (R)-DHNKAntagonistN/AKi = 74.55RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki = 42.1RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 59.7RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (2S,6S)-HNKAntagonistN/AKi = 21.19RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki > 10RBA—[3H]MK-801 bindingWhole brainRatZanos et al. (2016)
    Ki = 7.34RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 = 10.4RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    (2R,6R)-HNKNo effectN/AKi > 100RBA—[3H]MK-801 bindingWhole brainRatMoaddel et al. (2013)
    Ki > 10RBA—[3H]MK-801 bindingWhole brainRatZanos et al. (2016)
    Ki > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    AntagonistAntidepressantIC50 > 50Whole-cell recordingsHippocampal neuron cultureMouseSuzuki et al. (2017)
    (2R,6S)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2S,6R)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2R,5R)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2S,5S)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2R,5S)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2S,5R)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2R,4R)-HNKN/AN/AKi > 100RBA —[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2S,4S)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2R,4S)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    (2S,4R)-HNKN/AN/AKi > 100RBA—[3H]MK-801 bindingWhole brain (excluding cerebellum)RatMorris et al. (2017)
    IC50 > 100
    D-serine(S)-KETTransport inhibitorAntidepressant effects and dissociative side effectsEC50 = 0.82 ± 0.29a (intracellular); 0.76 ± 0.13a (extracellular)CE-LIF (intracellular); LC-MS (extracellular)PC-12 cellsRat-derived cell lineSingh et al. (2015)
    EC50 = 0.46 ± 0.25a (intracellular); 0.57 ± 0.32a (extracellular)CE-LIF (intracellular); LC-MS (extracellular)1321N1 cellsHuman-derived cell lineSingh et al. (2015)
    (R)-KETα7 nAChR inhibitionIC50 = 0.94 ± 0.16a (intracellular); 0.70 ± 0.10a (extracellular)CE-LIF (intracellular); LC-MS (extracellular)PC-12 cellsRat-derived cell lineSingh et al. (2015)
    IC50 = 0.75 ± 0.27a (intracellular); 0.88 ± 0.25a (extracellular)CE-LIF (intracellular); LC-MS (extracellular)1321N1 cellsHuman-derived cell lineSingh et al. (2015)
    DHNKIC50 = 0.115 (intracellular)CE-LIFPC-12 cellsRat-derived cell lineSingh et al. (2013)
    IC50 = 0.035CE-LIF1321N1 cellsHuman-derived cell lineSingh et al. (2013)
    (intracellular)
    (2S,6S)-HNKIC50 = 0.00018 ± 0.00004a (intracellular)CE-LIFPC-12 cellsRat-derived cell lineSingh et al. (2016c)
    (2R,6R)-HNKIC50 = 0.00068 ± 0.00009a (intracellular)CE-LIFPC-12 cellsRat-derived cell lineSingh et al. (2016c)
    HCN1(R,S)-KETInhibitorAnesthesia, antidepressant effectsEC50 = 8.2–15.6Whole-cell recordingMouse channels expressed in HEK293 cellsMouseChen et al. (2009)
    (S)-KETEC50 = 4.1–7.4Whole-cell recordingMouse channels expressed in HEK293 cellsMouseChen et al. (2009)
    GABA uptake(R,S)-KETReversible noncompetitive inhibitorN/AKi = 6.2 ± 1.1a;RBA—[3H]GABA bindingStriatal synaptosomesRatMantz et al. (1995)
    InhibitorAnesthesia (due to observed increased GABA content)IC50 = ∼400RBA—[3H]GABA bindingCultured neurons from cerebral hemispheresMouseWood and Hertz (1980)
    IC50 > 1000RBA—[3H]GABA bindingCultured astrocytes from cerebral hemispheresMouseWood and Hertz (1980)
    IC50 > 1000RBA—[3H]GABA bindingBrain synaptosomesMouseWood and Hertz 1980)
    Reversible noncompetitive inhibitorN/AIC50 = 50RBA—[3H]GABA bindingStriatal synaptosomesRatMantz et al. (1995)
    GABAAR(R,S)-KETPositive modulatorN/AEC50 = 1200 ± 600Whole-cell recordingHuman receptor expressed in HEK293 cellsHumanFlood and Krasowski (2000)
    No effectN/AEC50 > 1000Human receptor expressed in Xenopus oocytesHumanHuman receptor expressed in Xenopus oocytesYamakura et al. (2000)
    M1 mAChR(R,S)-KETN/RN/AKi = 45RBAHuman receptor expressed in CHO cellsHumanHirota et al. (2002)
    AntagonistIC50 = 5.7Two-microelectrode recordingRat receptor expressed in Xenopus oocytesRatDurieux (1995)
    M2 mAChR(R,S)-KETN/RN/AKi = 294RBAHuman receptor expressed in CHO cellsHumanHirota et al. (2002)
    M3 mAChR(R,S)-KETN/RN/AKi = 246RBAHuman receptor expressed in CHO cellsHumanHirota et al. (2002)
    nAChR (muscle type)(R,S)-KETAntagonistN/AKi = 16.5 ± 0.7a (resting); Ki = 13.1 ± 1.8a (desensitized)RBA—[3H]TCP bindingAChR native membranesT. californicaArias et al. (2002)
    Ki = 20.9 ± 3.0aRBA—[3H]tetracaine bindingAChR native membranesT. californicaArias et al. (2002)
    No effectNo effectRBA—[14C]amobarbital bindingAChR native membranesT. californicaArias et al. (2002)
    (S)-KETAntagonistN/AKi = 18.2 ± 1.2a (resting); Ki = 15.4 ± 2.3a (desensitized)RBA—[3H]TCP bindingAChR native membranesT. californicaArias et al. (2002)
    Ki = 19.9 ± 2.8aRBA—[3H]tetracaine bindingAChR native membranesT. californicaArias et al. (2002)
    Ki = 430 ± 330aRBA—[14C]amobarbital bindingAChR native membranesT. californicaArias et al. (2002)
    α nAChR(R,S)-KETAntagonistN/AEC50 = 18.7 ± 7.4aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    (S)-KETAntagonistEC50 = 9.7 ± 2.2aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    β nAChR(R,S)-KETAntagonistEC50 = 15.2 ± 3.6aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    (S)-KETAntagonistEC50 = 7.4 ± 4.5aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    γ nAChR(R,S)-KETAntagonistEC50 = 20.4 ± 10.1aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    (S)-KETAntagonistEC50 = 6.6 ± 2.9aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    δ nAChR(R,S)-KETAntagonistEC50 = 19.4 ± 6.5aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    (S)-KETAntagonistEC50 = 8.5 ± 2.4aRBA—[125I]TID photoincorporationAChR native membranesT. californicaArias et al. (2002)
    α2β2 nAChR(R,S)-KETAntagonistN/AIC50 = 92Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    α4β4 nAChR(R,S)-KETAntagonistN/AIC50 = 0.24 ± 0.03Whole-cell recordingChicken receptor expressed in Xenopus oocytesChickenFlood and Krasowski (2000)
    AntagonistN/AIC50 = 18Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    α2β4 nAChR(R,S)-KETAntagonistN/AIC50 = 29Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    α4β2 nAChR(R,S)-KETAntagonistN/AIC50 = 72Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    AntagonistN/AIC50 = 50 ± 4Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanCoates and Flood (2001)
    α7 nAChR(R,S)-KETAntagonistAntidepressant effectsIC50 = 20 ± 2Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanCoates and Flood (2001)
    IC50 = 17.3 ± 2Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanHo and Flood (2004)
    (R,S)-DHNKAntagonistIC50 = 0.055 ± 0.006Whole-cell recordingKXα7R1 cells (express rat receptors)RatMoaddel et al. (2013)
    α3β2 nAChR(R,S)-KETAntagonistN/AIC50 = 50Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    α3β4 nAChR(R,S)-KETAntagonistN/AIC50 = 9.5Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    AntagonistIC50 = 3.1Whole-cell recordingKXα3β4R2 cells (express rat receptors)RatMoaddel et al. (2013)
    (R,S)-norKETAntagonistIC50 = 9.1Whole-cell recordingKXα3β4R2 cells (express rat receptors)RatMoaddel et al. (2013)
    (R,S)-DHNKNo significant effectIC50 > 200Whole-cell recordingKXα3β4R2 cells (express rat receptors)RatMoaddel et al. (2013)
    (2S,6S)-HNKIC50 > 200Whole-cell recordingKXα3β4R2 cells (express rat receptors)RatMoaddel et al. (2013)
    (2R,6R)-HNKIC50 > 200Whole-cell recordingKXα3β4R2 cells (express rat receptors)RatMoaddel et al. (2013)
    D1–5R(S)-KETN/AN/ANo functional effect up to 10 μMRBAHuman receptor expressed in HEKT (for D1/3/5R), or stable fibroblast (for D2R) cellsHumanCan et al. (2016)
    (R)-KET
    (S)-norKET
    (R)-norKET
    (S)-DHNK
    (R)-DHNK
    (2S,6S)-HNK
    (2R,6R)-HNK
    D2R(R,S)-KETPartial agonistPsychotomimetic effectsKi = 1.0 ± 0.15RBAStriatumRatKapur and Seeman (2001, 2002)
    Ki = 0.5 ± 0.2 EC50 = 0.9 ± 0.4RBAHuman D2R expressed in CHO cellsHumanKapur and Seeman (2002)
    EC50 = 0.4RBA/[35S]-GTPγSHuman D2R expressed in CHO cellsHumanSeeman and Kapur (2003)
    Ki = 0.055 ± 0.012RBAHuman receptor expressed in CHO cellsHumanSeeman et al. (2005)
    AntagonistN/AIC50 = 2RBA—[35S]-GTPγSHuman D2R expressed in CHO cellsHumanSeeman and Kapur (2003)
    DAT(R,S)-KETReversible, noncompetitive inhibitionN/AIC50 = 4.6RBA—[3H]dopamine uptakeStriatumRatKeita et al. (1996)
    Uptake inhibitorN/AKi = 62.9 ± 2.3aRUA—[3H]dopamine uptakeRat transporter expressed in HEK293 cellsRatNishimura et al. (1998)
    (S)-KETNo binding or functional activity up to 10 μMN/AN/ARBAHuman transporter expressed in HEK cellsHumanCan et al. (2016)
    (R)-KET
    (S)-norKET
    (R)-norKET
    (S)-DHNK
    (R)-DHNK
    (2S,6S)-HNK
    (2R,6R)-HNK
    5-HT2R(R,S)-KETN/RAnalgesic effectsKi = 15 ± 5RBAFrontal cortexRatKapur and Seeman (2002)
    5-HT3R(R,S)-KETAntagonistN/AKi = 96.9 ± 3.5RBA—[3H]BRL43,694Neuroblastoma cell cultures (N1E-115)MouseAppadu and Lambert (1996)
    5-HT3R(R,S)-KETCompetitive antagonistN/AKi = 420 ± 605-HT–induced currents: whole-cell recordingsHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    Noncompetitive antagonistN/AIC50i = 910 ± 305-HT–induced currents: whole-cell recordingsHuman receptor expressed in Xenopus oocytesHumanYamakura et al. (2000)
    5-HT3AR(R,S)-KETAntagonistN/AIC50 > 100Whole-cell recordingHuman receptor expressed in Xenopus oocytesHumanHo and Flood (2004)
    SERT(R,S)-KETUptake inhibitorN/AIC50 = 20.2 ± 2.75RUA—[3H]5-HT uptakeBrain (except cerebellum)RatMartin et al. (1988)
    N/AIC50 = 18.8RUA—[3H]paroxetineBrain (except cerebellum)RatMartin et al. (1990)
    N/AKi = 161.7 ± 28.3aRUA—[3H]serotoninRat transporter expressed in HEK293 cellsRatNishimura et al. (1998)
    IC50 = 75 ± 8RUA—[3H]5-HT uptakeCortical synaptosomesRatAzzaro and Smith (1977)
    IC50 = 125.2RUA—[3H]5-HT uptakeNE transporter expressed in HEK293 cellsHumanZhao and Sun (2008)
    (S)-KETN/ANo binding or functional activity up to 10 μMRBAHuman transporter expressed in HEK cellsHumanCan et al. (2016)
    (R)-KET
    (S)-norKET
    (R)-norKET
    (S)-DHNK
    (R)-DHNK
    (2S,6S)-HNK
    (2R,6R)-HNK
    NET(R,S)-KETUptake inhibitorN/AKi = 66.8 ± 25.9aRUA—[3H]NEHuman transporter expressed in HEK293 cellsHumanNishimura et al. (1998)
    100 μM—estimated ∼50% noncompetitive inhibitionRUA—[3H]NEBovine adrenal medullary cellsBovineHara et al. (1998a)
    10–100 μM—estimated ∼50% noncompetitive inhibitionRUA—[3H]NEXenopus oocytes expressing bovine NE transportersBovineHara et al. (1998a)
    300 μM—competitive inhibitionRUA—[3H]desipraminePlasma membranes of bovine adrenal medullaBovineHara et al. (1998a)
    IC50 = 290.7RUA—[3H]NENE transporter expressed in HEK293 cellsHumanZhao and Sun (2008)
    (S)-KETN/ANo binding or functional activity up to 10 μMRBAHuman transporter expressed in HEK cellsHumanCan et al. (2016)
    (R)-KET
    (S)-norKET
    (R)-norKET
    (S)-DHNK
    (R)-DHNK
    (2S,6S)-HNK
    (2R,6R)-HNK
    µ opioid receptor(R,S)-KETAgonistAnalgesiaKi = 42.1RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    (S)-KETAgonistKi = 28.6RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 11RBA—[3H]DAMGOWhole brainRatHustveit et al. (1995)
    (R)-KETAgonistKi = 83.8RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 28RBA—[3H]DAMGOWhole brainRatHustveit et al. (1995)
    κ opioid receptor(R,S)-KETAgonistKi = 28.1RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 25.0; EC50 = 29.0RBA—[35S]-GTPγSHuman receptor expressed in CHO cellsHumanNemeth et al. (2010)
    (S)-KETAgonistKi = 23.7RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 24RBA—[3H]U69,593Whole brainRatHustveit et al. (1995)
    (R)-KETAgonistKi = 60.0RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 100RBA—[3H]U69,593Whole brainRatHustveit et al. (1995)
    δ opioid receptor(R,S)-KETAgonistKi = 272RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    (S)-KETAgonistKi = 205RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 130RBA—[3H]DPDPEWhole brainRatHustveit et al. (1995)
    (R)-KETAgonistKi = 286RBA—[3H]DPNHuman receptor expressed in CHO cellsHumanHirota et al. (1999)
    Ki = 130RBA—[3H]DPDPEWhole brainRatHustveit et al. (1995)
    σ1/2R(R,S)-KETN/RAntidepressant effectsIC50 = 66.0 ± 10.0RBA – [3H] + SKF10,047Spinal cordRatSmith et al. (1987)
    Ki = 0.15RBA—[3H] + SKF10,047Whole brainRatHustveit et al. (1995)
    Ki > 10RBA—[3H]DTGRat glioma hybrid cells NG108-15RatGeorg and Friedl (1991)
    (R)-KETKi = 19RBA—[3H] + SKF10,047Whole brainRatHustveit et al. (1995)
    (S)-KETKi = 131RBA—[3H] + SKF10,047Whole brainRatHustveit et al. (1995)
    σ1R(R,S)-KETKi = 139.60 ± 6.13RBA—[3H] (+) pentazocineLiver membraneRatRobson et al. (2012)
    σ2R(R,S)-KETKi = 26.30 ± 2.98RBA—[3H]di-o-tolylguanidineLiver membraneRatRobson et al. (2012)
    TTX-sensitive VGSC(R,S)-KETAntagonistLocal anesthesiaIC50 = 146.7 ± 8.4 (tonic)Whole-cell recordingDorsal root ganglionRatZhou and Zhao (2000)
    TTX-resistant VGSC(R,S)-KETAntagonistIC50 = 866.2 ± 34.7 (tonic), 314.8 ± 12.4 (phasic)Whole-cell recordingDorsal root ganglionRatZhou and Zhao (2000)
    VGSC(R,S)-KETAntagonistIC50 = 800 (tonic), 2300 (phasic)Two-microelectrode recordingRat channels expressed in Xenopus oocytesRatWagner et al. (2001)
    IC50 = 222.022Na+-stimulated influx (measure sodium uptake)Brain (minus cerebellum) synaptoneurosomal fractionsRatAllaoua and Chicheportiche (1989)
    Ki = 11.5
    ED50 = 1100Single channel recordingsCortical synaptosome bilayerHumanFrenkel and Urban (1992)
    (S)-KETAntagonistIC50 = 240 ± 60a (neuronal), 59 ± 10a (skeletal)Whole-cell recordingRat channels expressed in HEK293 cellsRatHaeseler et al. (2003)
    (R)-KETAntagonistIC50 = 333 ± 93a (neuronal), 181 ± 49a (skeletal)Whole-cell recordingRat channels expressed in HEK293 cellsRatHaeseler et al. (2003)
    L-type VDCC(R,S)-KETAntagonistAntidepressant effectsIC50 = 1000Whole-cell recordingTracheal smooth musclePigYamakage et al. (1995)
    (R,S)-KETIC50 = 9.2Whole-cell recordingAtrial myocytesBullfrogHatakeyama et al. (2001)
    • CE-LIF, capillary electrophoresis-laser-induced fluorescence; D1–5R, dopamine receptor subtypes 1–5; DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DAT, dopamine transporter; DPDPE, [D-Pen2,D-Pen5]enkephalin; DPN, diprenorphine; DTG, 1,3-Di-o-tolylguanidine; EPSP, excitatory postsynaptic potential; FLIPR, fluorescence imaging plate reader; GABAAR, GABA receptor A; GTPγS, guanosine 5′-3-O-(thio)triphosphate; HEK, human embryonic kidney cells; 5-HT2R, serotonin receptor subtype 2; KET, ketamine; LC-MS, liquid chromatography–mass spectrometry; NMDA, N-methyl-D-aspartate; norKET, norketamine; NE, norepinephrine; RBA, radioligand-binding assay; RUA, radioligand uptake assay; TCP, [1-(2-thienyl)cyclohexyl] piperidine; TID, 3-(Trifluoromethyl)-3-(3-iodophenyl)diazirine; TTX, tetrodotoxin; VGSC, voltage-gated sodium channel.

    • ↵a Values reported as mean ± S.D.

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Pharmacological Reviews: 70 (3)
Pharmacological Reviews
Vol. 70, Issue 3
1 Jul 2018
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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate and Todd D. Gould
Pharmacological Reviews July 1, 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198

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Review ArticleReview Article

Ketamine and Ketamine Metabolite Pharmacology

Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate and Todd D. Gould
Pharmacological Reviews July 1, 2018, 70 (3) 621-660; DOI: https://doi.org/10.1124/pr.117.015198
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