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. 2018 Jul;70(3):621–660. doi: 10.1124/pr.117.015198

TABLE 3.

Molecular targets of ketamine and its metabolites

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

Receptor/Target Drug Action Proposed Clinical Relevance Affinity/ Potency (μM) Method Tissue/System Species Reference
NMDAR (R,S)-KET Antagonist Anesthesia, antidepressant effects, amnesia, dissociative effects, abuse potential, cognitive impairment Ki = 0.49 ± 0.05 RBA—[3H]MK-801 binding Cerebral cortex Rat Wong et al. (1986)
Ki = 1.09 RBA—[3H]MK-801 binding Brain Rat Wong et al. (1988)
Ki = 1.09 RBA—[3H]MK-801 binding Brain Rat Wong et al. (1988)
Ki = 1.93 RBA—[3H]TCP binding Brain Rat Wong et al. (1988)
Ki = 0.42 ± 0.03 RBA—[3H]MK-801 binding Cortex Human Kornhuber et al. (1989)
Ki = 0.18 ± 0.03 RBA—[3H]MK-801 binding (no added glutamate or glycine) Brain Rat Reynolds and Miller (1989)
Ki = 0.24 ± 0.10 RBA—[3H]MK-801 binding (added 100 µM glutamate and 30 µM glycine) Brain Rat Reynolds and Miller (1989)
Ki = 0.58 ± 0.07 RBA—[3H]MK-801 binding Brain Mouse Sharif et al. (1991)
Ki = 0.76 ± 0.047 RBA—[3H]MK-801 binding Brain Guinea pig Sharif et al. (1991)
Ki = 0.48 ± 0.1 RBA—[3H]MK-801 binding Brain Dog Sharif et al. (1991)
Ki = 0.71 ± 0.06 RBA—[3H]MK-801 binding Cortex Dog Sharif et al. (1991)
Ki = 0.6 ± 0.04 RBA—[3H]MK-801 binding Spinal cord Rat Sharif et al. (1991)
Ki > 10 RBA—[3H]TCP binding Rat glioma hybrid cells NG108-15 Rat Georg and Friedl (1991)
Ki = 1.19 ± 0.24 RBA—[3H]MK-801 binding Cortex Rat Bresink et al. (1995)
Ki = 0.20 ± 0.02 RBA—[3H]MK-801 binding Brain (synaptic membranes) Rat Parsons et al. (1995)
Ki = 1.0 ± 0.5 RBA—[125I]MK-801 binding Membranes from HEK293 cells transfected with GluN1/2A receptors Rat Lynch et al. (1995)
Ki = 2.5 ± 1.2 RBA—[125I]MK-801 binding Membranes from HEK293 cells transfected with GluN1/2B receptors Rat Lynch et al. (1995)
Ki = 2.51 ± 1.90 Autoradiographic binding—[3H]MK-801 Cerebellum Rat Bresink et al. (1995)
Ki = 0.5 ± 0.15 RBA—[3H]MK-801 binding Striatum Rat Kapur and Seeman (2001, 2002)
Ki = 0.92 RBA—[3H]MK-801 binding Brain membranes Rat Sun and Wessinger (2004)
Ki = 3.1 ± 0.3 RBA—[3H]MK-801 binding Striatum Rat Seeman et al. (2005)
Ki = 1.35 ± 0.43 RBA—[3H]MK-801 binding Cortex Rat Gilling et al. (2009)
Ki = 0.67 ± 0.15 RBA—[3H]MK-801 binding Cortex Human Gilling et al. (2009)
Ki = 1.47 ± 0.68 Whole-cell patch-clamp recordings—holding potential at −70 mV HEK293 cells transfected with GluN1/2A receptors Human Gilling et al. (2009)
Ki = 0.32 ± 0.02 RBA—[3H]MK-801 binding Forebrain Rat Wallach et al. (2016), Kang et al. (2017)
Ki = 0.25 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 3.91 RBA—[3H]TCP binding Rat brain (minus cerebellum) synaptoneurosomal fractions Rat Allaoua and Chicheportiche (1989)
IC50 = 5.4 ± 0.6 Autoradiographic binding—[3H]MK-801 Frontal cortex Rat Porter and Greenamyre (1995)
IC50 = 5.0 ± 0.6 Autoradiographic binding—[3H]MK-801 Striatum Rat Porter and Greenamyre (1995)
IC50 = 3.9 ± 0.5 Autoradiographic binding—[3H]MK-801 Entorhinal cortex Rat Porter and Greenamyre (1995)
IC50 = 6.7 ± 0.8 Autoradiographic binding—[3H]MK-801 Hippocampus (CA1) Rat Porter and Greenamyre (1995)
IC50 = 5.4 ± 0.6 Autoradiographic binding—[3H]MK-801 Dentate gyrus Rat Porter and Greenamyre (1995)
IC50 = 8.2 ± 0.6 Autoradiographic binding—[3H]MK-801 Cerebellar granule cell layer Rat Porter and Greenamyre (1995)
IC50 = 1.6 ± 0.01 Whole-cell patch-clamp recordings Cultured superior collicular neurones Rat Parsons et al. (1995)
IC50 > 10; 100 μM induced a 63% inhibition NMDA (10 μM)-evoked extracellular postsynaptic currents Ventral tegmental area Rat Wu and Johnson (1996)
IC50 = 1.03 ± 0.06 Glutamate (0.3 μM)-evoked GluN1/2A currents tsA201 cells Rat Glasgow et al. (2017)
IC50 = 0.89 ± 0.07 Glutamate (1 mM)-evoked GluN1/2A currents tsA201 cells Rat Glasgow et al. (2017)
IC50 = 0.59 ± 0.03 Glutamate (0.3 μM)-evoked GluN1/2B currents tsA201 cells Rat Glasgow et al. (2017)
IC50 = 0.43 ± 0.04 Glutamate (1 mM)-evoked GluN1/2B currents tsA201 cells Rat Glasgow et al. (2017)
IC50 = 0.43 ± 0.10 Whole-cell patch-clamp recordings Hippocampus Rat Parsons et al. (1996)
IC50 = 0.92 ± 0.21 Whole-cell patch-clamp recordings Striatum Rat Parsons et al. (1996)
2 mM Mg2+ Two-microelectrode recording Rat receptors expressed in Xenopus oocytes Rat Dravid et al. (2007)
GluN1/2A: IC50 = 3.31
GluN1/2B: IC50 = 0.93
GluN1/2C: IC50 = 1.65
GluN1/2D: IC50 = 2.42
IC50 = 7.97 FLIPR calcium influx assay HEK293 cells Human Gilling et al. (2009)
IC50 = 0.71 ± 0.03 Whole-cell patch-clamp recordings—holding potential at −70 mV Human Gilling et al. (2009)
IC50 = 6.05 ± 0.66 Whole-cell patch-clamp recordings—holding potential at 0 mV HEK293 cells transfected with GluN1/2A receptors Human Gilling et al. (2009)
Mg2+ free Whole-cell recordings Rat receptor expressed in HEK293 cells Rat Kotermanski 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 recordings Rat receptor expressed in HEK293 cells Rat Kotermanski 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 = 10 Extracellular recordings (EPSPs) Hippocampus (CA1) Rat Izumi and Zorumski (2014)
IC50 = 0.40 Whole-cell patch-clamp recordings Hippocampal neuron culture Rat Emnett et al. (2016)
IC50 = 0.51 ± 0.04 RBA—[3H]MK-801 binding Forebrain Rat Wallach et al. (2016), Kang et al. (2017)
IC50 = 0.35 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(S)-KET Antagonist Anesthesia, antidepressant effects, dissociative effects, cognitive impairment Ki = 0.30 ± 0.013 RBA—[3H]MK-801 binding Cortex Rat Ebert et al. (1997)
Ki = 0.69 ± 0.09 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 0.42 ± 0.04 RBA—[3H]MK-801 binding Cortex Pig Bonifazi et al. (2015)
Ki = 0.44 ± 0.10 RBA—[3H]MK-801 binding Cortex Pig Temme et al. (2018)
IC50 = 1.6–1.9 RBA—[3H]MK-801 binding Hippocampus (two brain samples only) Human Oye et al. (1992)
IC50 = 1.5–2.8 RBA—[3H]MK-801 binding Frontal cortex (two brain samples only) Human Oye et al. (1992)
IC50 = 1.6–2.1 RBA—[3H]MK-801 binding Occibital cortex (two brain samples only) Human Oye et al. (1992)
IC50 = 0.80 Whole-cell patch-clamp recordings Hippocampus Rat Zeilhofer et al. (1992)
IC50 = 0.9 ± 1.4 NMDA (μM)-evoked currents Cortex Rat Ebert et al. (1997)
2 mM Mg2+ Two-microelectrode recording Rat receptors expressed in Xenopus ooctyes Rat Dravid et al. (2007)
GluN1/2A: IC50 = 16.10
GluN1/2B: IC50 = 1.55
GluN1/2C: IC50 = 1.11
GluN1/2D: IC50 = 1.50
(R)-KET Antagonist Anesthesia, antidepressant effects Ki = 1.40 ± 0.1 RBA—[3H]MK-801 binding Cortex Rat Ebert et al. (1997)
Ki = 2.57 ± 0.28 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 1.79 ± 0.31 RBA—[3H]MK-801 binding Cortex Pig Temme et al. (2018)
IC50 = 7.2–10 RBA—[3H]MK-801 binding Hippocampus (two brain samples only) Human Oye et al. (1992)
IC50 = 8.2–13.7 RBA—[3H]MK-801 binding Frontal cortex (two brain samples only) Human Oye et al. (1992)
IC50 = 10.9–11.4 RBA—[3H]MK-801 binding Occibital cortex (two brain samples only) Human Oye et al. (1992)
IC50 = 1.53 Whole-cell patch-clamp recordings Hippocampus Rat Zeilhofer et al. (1992)
IC50 = 3.0 ± 1.4 NMDA (μM)-evoked currents Cortex Rat Ebert et al. (1997)
(R,S)-norKET Antagonist Anesthesia Ki = 3.60 ± 0.49 RBA—[3H]MK-801 binding Cortex Rat Ebert et al. (1997)
2 mM Mg2+ Two-microelectrode recording Rat receptors expressed in Xenopus ooctyes Rat Dravid et al. (2007)
GluN1/2A: IC50 = 50.90
GluN1/2B: IC50 = 8.74
GluN1/2C: IC50 = 5.6
GluN1/2D: IC50 = 7.5
IC50 = 2.00 Whole-cell recordings Hippocampal neuron culture Rat Emnett et al. (2016)
(S)-norKET Antagonist Ki = 1.7 ± 0.050 RBA—[3H]MK-801 binding Cortex Rat Ebert et al. (1997)
Ki = 2.25 ± 0.22 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 0.87 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 3.0 ± 0.8 NMDA (μM)-evoked currents Cortex Rat Ebert et al. (1997)
IC50 = 1.23 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(R)-norKET Antagonist Ki = 13 ± 1.8 RBA—[3H]MK-801 binding Cortex Rat Ebert et al. (1997)
Ki = 26.46 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 0.60 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 39.0 ± 1.4 NMDA (μM)-evoked currents Cortex Rat Ebert et al. (1997)
IC50 = 0.85 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(S)-DHNK Antagonist N/A Ki = 38.95 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 29.7 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 42.0 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(R)-DHNK Antagonist N/A Ki = 74.55 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki = 42.1 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 59.7 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(2S,6S)-HNK Antagonist N/A Ki = 21.19 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki > 10 RBA—[3H]MK-801 binding Whole brain Rat Zanos et al. (2016)
Ki = 7.34 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 = 10.4 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
(2R,6R)-HNK No effect N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain Rat Moaddel et al. (2013)
Ki > 10 RBA—[3H]MK-801 binding Whole brain Rat Zanos et al. (2016)
Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
Antagonist Antidepressant IC50 > 50 Whole-cell recordings Hippocampal neuron culture Mouse Suzuki et al. (2017)
(2R,6S)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2S,6R)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2R,5R)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2S,5S)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2R,5S)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2S,5R)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2R,4R)-HNK N/A N/A Ki > 100 RBA —[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2S,4S)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2R,4S)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
(2S,4R)-HNK N/A N/A Ki > 100 RBA—[3H]MK-801 binding Whole brain (excluding cerebellum) Rat Morris et al. (2017)
IC50 > 100
D-serine (S)-KET Transport inhibitor Antidepressant effects and dissociative side effects EC50 = 0.82 ± 0.29a (intracellular); 0.76 ± 0.13a (extracellular) CE-LIF (intracellular); LC-MS (extracellular) PC-12 cells Rat-derived cell line Singh et al. (2015)
EC50 = 0.46 ± 0.25a (intracellular); 0.57 ± 0.32a (extracellular) CE-LIF (intracellular); LC-MS (extracellular) 1321N1 cells Human-derived cell line Singh et al. (2015)
(R)-KET α7 nAChR inhibition IC50 = 0.94 ± 0.16a (intracellular); 0.70 ± 0.10a (extracellular) CE-LIF (intracellular); LC-MS (extracellular) PC-12 cells Rat-derived cell line Singh et al. (2015)
IC50 = 0.75 ± 0.27a (intracellular); 0.88 ± 0.25a (extracellular) CE-LIF (intracellular); LC-MS (extracellular) 1321N1 cells Human-derived cell line Singh et al. (2015)
DHNK IC50 = 0.115 (intracellular) CE-LIF PC-12 cells Rat-derived cell line Singh et al. (2013)
IC50 = 0.035 CE-LIF 1321N1 cells Human-derived cell line Singh et al. (2013)
(intracellular)
(2S,6S)-HNK IC50 = 0.00018 ± 0.00004a (intracellular) CE-LIF PC-12 cells Rat-derived cell line Singh et al. (2016c)
(2R,6R)-HNK IC50 = 0.00068 ± 0.00009a (intracellular) CE-LIF PC-12 cells Rat-derived cell line Singh et al. (2016c)
HCN1 (R,S)-KET Inhibitor Anesthesia, antidepressant effects EC50 = 8.2–15.6 Whole-cell recording Mouse channels expressed in HEK293 cells Mouse Chen et al. (2009)
(S)-KET EC50 = 4.1–7.4 Whole-cell recording Mouse channels expressed in HEK293 cells Mouse Chen et al. (2009)
GABA uptake (R,S)-KET Reversible noncompetitive inhibitor N/A Ki = 6.2 ± 1.1a; RBA—[3H]GABA binding Striatal synaptosomes Rat Mantz et al. (1995)
Inhibitor Anesthesia (due to observed increased GABA content) IC50 = ∼400 RBA—[3H]GABA binding Cultured neurons from cerebral hemispheres Mouse Wood and Hertz (1980)
IC50 > 1000 RBA—[3H]GABA binding Cultured astrocytes from cerebral hemispheres Mouse Wood and Hertz (1980)
IC50 > 1000 RBA—[3H]GABA binding Brain synaptosomes Mouse Wood and Hertz 1980)
Reversible noncompetitive inhibitor N/A IC50 = 50 RBA—[3H]GABA binding Striatal synaptosomes Rat Mantz et al. (1995)
GABAAR (R,S)-KET Positive modulator N/A EC50 = 1200 ± 600 Whole-cell recording Human receptor expressed in HEK293 cells Human Flood and Krasowski (2000)
No effect N/A EC50 > 1000 Human receptor expressed in Xenopus oocytes Human Human receptor expressed in Xenopus oocytes Yamakura et al. (2000)
M1 mAChR (R,S)-KET N/R N/A Ki = 45 RBA Human receptor expressed in CHO cells Human Hirota et al. (2002)
Antagonist IC50 = 5.7 Two-microelectrode recording Rat receptor expressed in Xenopus oocytes Rat Durieux (1995)
M2 mAChR (R,S)-KET N/R N/A Ki = 294 RBA Human receptor expressed in CHO cells Human Hirota et al. (2002)
M3 mAChR (R,S)-KET N/R N/A Ki = 246 RBA Human receptor expressed in CHO cells Human Hirota et al. (2002)
nAChR (muscle type) (R,S)-KET Antagonist N/A Ki = 16.5 ± 0.7a (resting); Ki = 13.1 ± 1.8a (desensitized) RBA—[3H]TCP binding AChR native membranes T. californica Arias et al. (2002)
Ki = 20.9 ± 3.0a RBA—[3H]tetracaine binding AChR native membranes T. californica Arias et al. (2002)
No effect No effect RBA—[14C]amobarbital binding AChR native membranes T. californica Arias et al. (2002)
(S)-KET Antagonist N/A Ki = 18.2 ± 1.2a (resting); Ki = 15.4 ± 2.3a (desensitized) RBA—[3H]TCP binding AChR native membranes T. californica Arias et al. (2002)
Ki = 19.9 ± 2.8a RBA—[3H]tetracaine binding AChR native membranes T. californica Arias et al. (2002)
Ki = 430 ± 330a RBA—[14C]amobarbital binding AChR native membranes T. californica Arias et al. (2002)
α nAChR (R,S)-KET Antagonist N/A EC50 = 18.7 ± 7.4a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
(S)-KET Antagonist EC50 = 9.7 ± 2.2a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
β nAChR (R,S)-KET Antagonist EC50 = 15.2 ± 3.6a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
(S)-KET Antagonist EC50 = 7.4 ± 4.5a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
γ nAChR (R,S)-KET Antagonist EC50 = 20.4 ± 10.1a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
(S)-KET Antagonist EC50 = 6.6 ± 2.9a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
δ nAChR (R,S)-KET Antagonist EC50 = 19.4 ± 6.5a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
(S)-KET Antagonist EC50 = 8.5 ± 2.4a RBA—[125I]TID photoincorporation AChR native membranes T. californica Arias et al. (2002)
α2β2 nAChR (R,S)-KET Antagonist N/A IC50 = 92 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
α4β4 nAChR (R,S)-KET Antagonist N/A IC50 = 0.24 ± 0.03 Whole-cell recording Chicken receptor expressed in Xenopus oocytes Chicken Flood and Krasowski (2000)
Antagonist N/A IC50 = 18 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
α2β4 nAChR (R,S)-KET Antagonist N/A IC50 = 29 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
α4β2 nAChR (R,S)-KET Antagonist N/A IC50 = 72 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
Antagonist N/A IC50 = 50 ± 4 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Coates and Flood (2001)
α7 nAChR (R,S)-KET Antagonist Antidepressant effects IC50 = 20 ± 2 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Coates and Flood (2001)
IC50 = 17.3 ± 2 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Ho and Flood (2004)
(R,S)-DHNK Antagonist IC50 = 0.055 ± 0.006 Whole-cell recording KXα7R1 cells (express rat receptors) Rat Moaddel et al. (2013)
α3β2 nAChR (R,S)-KET Antagonist N/A IC50 = 50 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
α3β4 nAChR (R,S)-KET Antagonist N/A IC50 = 9.5 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
Antagonist IC50 = 3.1 Whole-cell recording KXα3β4R2 cells (express rat receptors) Rat Moaddel et al. (2013)
(R,S)-norKET Antagonist IC50 = 9.1 Whole-cell recording KXα3β4R2 cells (express rat receptors) Rat Moaddel et al. (2013)
(R,S)-DHNK No significant effect IC50 > 200 Whole-cell recording KXα3β4R2 cells (express rat receptors) Rat Moaddel et al. (2013)
(2S,6S)-HNK IC50 > 200 Whole-cell recording KXα3β4R2 cells (express rat receptors) Rat Moaddel et al. (2013)
(2R,6R)-HNK IC50 > 200 Whole-cell recording KXα3β4R2 cells (express rat receptors) Rat Moaddel et al. (2013)
D1–5R (S)-KET N/A N/A No functional effect up to 10 μM RBA Human receptor expressed in HEKT (for D1/3/5R), or stable fibroblast (for D2R) cells Human Can et al. (2016)
(R)-KET
(S)-norKET
(R)-norKET
(S)-DHNK
(R)-DHNK
(2S,6S)-HNK
(2R,6R)-HNK
D2R (R,S)-KET Partial agonist Psychotomimetic effects Ki = 1.0 ± 0.15 RBA Striatum Rat Kapur and Seeman (2001, 2002)
Ki = 0.5 ± 0.2 EC50 = 0.9 ± 0.4 RBA Human D2R expressed in CHO cells Human Kapur and Seeman (2002)
EC50 = 0.4 RBA/[35S]-GTPγS Human D2R expressed in CHO cells Human Seeman and Kapur (2003)
Ki = 0.055 ± 0.012 RBA Human receptor expressed in CHO cells Human Seeman et al. (2005)
Antagonist N/A IC50 = 2 RBA—[35S]-GTPγS Human D2R expressed in CHO cells Human Seeman and Kapur (2003)
DAT (R,S)-KET Reversible, noncompetitive inhibition N/A IC50 = 4.6 RBA—[3H]dopamine uptake Striatum Rat Keita et al. (1996)
Uptake inhibitor N/A Ki = 62.9 ± 2.3a RUA—[3H]dopamine uptake Rat transporter expressed in HEK293 cells Rat Nishimura et al. (1998)
(S)-KET No binding or functional activity up to 10 μM N/A N/A RBA Human transporter expressed in HEK cells Human Can et al. (2016)
(R)-KET
(S)-norKET
(R)-norKET
(S)-DHNK
(R)-DHNK
(2S,6S)-HNK
(2R,6R)-HNK
5-HT2R (R,S)-KET N/R Analgesic effects Ki = 15 ± 5 RBA Frontal cortex Rat Kapur and Seeman (2002)
5-HT3R (R,S)-KET Antagonist N/A Ki = 96.9 ± 3.5 RBA—[3H]BRL43,694 Neuroblastoma cell cultures (N1E-115) Mouse Appadu and Lambert (1996)
5-HT3R (R,S)-KET Competitive antagonist N/A Ki = 420 ± 60 5-HT–induced currents: whole-cell recordings Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
Noncompetitive antagonist N/A IC50i = 910 ± 30 5-HT–induced currents: whole-cell recordings Human receptor expressed in Xenopus oocytes Human Yamakura et al. (2000)
5-HT3AR (R,S)-KET Antagonist N/A IC50 > 100 Whole-cell recording Human receptor expressed in Xenopus oocytes Human Ho and Flood (2004)
SERT (R,S)-KET Uptake inhibitor N/A IC50 = 20.2 ± 2.75 RUA—[3H]5-HT uptake Brain (except cerebellum) Rat Martin et al. (1988)
N/A IC50 = 18.8 RUA—[3H]paroxetine Brain (except cerebellum) Rat Martin et al. (1990)
N/A Ki = 161.7 ± 28.3a RUA—[3H]serotonin Rat transporter expressed in HEK293 cells Rat Nishimura et al. (1998)
IC50 = 75 ± 8 RUA—[3H]5-HT uptake Cortical synaptosomes Rat Azzaro and Smith (1977)
IC50 = 125.2 RUA—[3H]5-HT uptake NE transporter expressed in HEK293 cells Human Zhao and Sun (2008)
(S)-KET N/A No binding or functional activity up to 10 μM RBA Human transporter expressed in HEK cells Human Can et al. (2016)
(R)-KET
(S)-norKET
(R)-norKET
(S)-DHNK
(R)-DHNK
(2S,6S)-HNK
(2R,6R)-HNK
NET (R,S)-KET Uptake inhibitor N/A Ki = 66.8 ± 25.9a RUA—[3H]NE Human transporter expressed in HEK293 cells Human Nishimura et al. (1998)
100 μM—estimated ∼50% noncompetitive inhibition RUA—[3H]NE Bovine adrenal medullary cells Bovine Hara et al. (1998a)
10–100 μM—estimated ∼50% noncompetitive inhibition RUA—[3H]NE Xenopus oocytes expressing bovine NE transporters Bovine Hara et al. (1998a)
300 μM—competitive inhibition RUA—[3H]desipramine Plasma membranes of bovine adrenal medulla Bovine Hara et al. (1998a)
IC50 = 290.7 RUA—[3H]NE NE transporter expressed in HEK293 cells Human Zhao and Sun (2008)
(S)-KET N/A No binding or functional activity up to 10 μM RBA Human transporter expressed in HEK cells Human Can et al. (2016)
(R)-KET
(S)-norKET
(R)-norKET
(S)-DHNK
(R)-DHNK
(2S,6S)-HNK
(2R,6R)-HNK
µ opioid receptor (R,S)-KET Agonist Analgesia Ki = 42.1 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
(S)-KET Agonist Ki = 28.6 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 11 RBA—[3H]DAMGO Whole brain Rat Hustveit et al. (1995)
(R)-KET Agonist Ki = 83.8 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 28 RBA—[3H]DAMGO Whole brain Rat Hustveit et al. (1995)
κ opioid receptor (R,S)-KET Agonist Ki = 28.1 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 25.0; EC50 = 29.0 RBA—[35S]-GTPγS Human receptor expressed in CHO cells Human Nemeth et al. (2010)
(S)-KET Agonist Ki = 23.7 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 24 RBA—[3H]U69,593 Whole brain Rat Hustveit et al. (1995)
(R)-KET Agonist Ki = 60.0 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 100 RBA—[3H]U69,593 Whole brain Rat Hustveit et al. (1995)
δ opioid receptor (R,S)-KET Agonist Ki = 272 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
(S)-KET Agonist Ki = 205 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 130 RBA—[3H]DPDPE Whole brain Rat Hustveit et al. (1995)
(R)-KET Agonist Ki = 286 RBA—[3H]DPN Human receptor expressed in CHO cells Human Hirota et al. (1999)
Ki = 130 RBA—[3H]DPDPE Whole brain Rat Hustveit et al. (1995)
σ1/2R (R,S)-KET N/R Antidepressant effects IC50 = 66.0 ± 10.0 RBA – [3H] + SKF10,047 Spinal cord Rat Smith et al. (1987)
Ki = 0.15 RBA—[3H] + SKF10,047 Whole brain Rat Hustveit et al. (1995)
Ki > 10 RBA—[3H]DTG Rat glioma hybrid cells NG108-15 Rat Georg and Friedl (1991)
(R)-KET Ki = 19 RBA—[3H] + SKF10,047 Whole brain Rat Hustveit et al. (1995)
(S)-KET Ki = 131 RBA—[3H] + SKF10,047 Whole brain Rat Hustveit et al. (1995)
σ1R (R,S)-KET Ki = 139.60 ± 6.13 RBA—[3H] (+) pentazocine Liver membrane Rat Robson et al. (2012)
σ2R (R,S)-KET Ki = 26.30 ± 2.98 RBA—[3H]di-o-tolylguanidine Liver membrane Rat Robson et al. (2012)
TTX-sensitive VGSC (R,S)-KET Antagonist Local anesthesia IC50 = 146.7 ± 8.4 (tonic) Whole-cell recording Dorsal root ganglion Rat Zhou and Zhao (2000)
TTX-resistant VGSC (R,S)-KET Antagonist IC50 = 866.2 ± 34.7 (tonic), 314.8 ± 12.4 (phasic) Whole-cell recording Dorsal root ganglion Rat Zhou and Zhao (2000)
VGSC (R,S)-KET Antagonist IC50 = 800 (tonic), 2300 (phasic) Two-microelectrode recording Rat channels expressed in Xenopus oocytes Rat Wagner et al. (2001)
IC50 = 222.0 22Na+-stimulated influx (measure sodium uptake) Brain (minus cerebellum) synaptoneurosomal fractions Rat Allaoua and Chicheportiche (1989)
Ki = 11.5
ED50 = 1100 Single channel recordings Cortical synaptosome bilayer Human Frenkel and Urban (1992)
(S)-KET Antagonist IC50 = 240 ± 60a (neuronal), 59 ± 10a (skeletal) Whole-cell recording Rat channels expressed in HEK293 cells Rat Haeseler et al. (2003)
(R)-KET Antagonist IC50 = 333 ± 93a (neuronal), 181 ± 49a (skeletal) Whole-cell recording Rat channels expressed in HEK293 cells Rat Haeseler et al. (2003)
L-type VDCC (R,S)-KET Antagonist Antidepressant effects IC50 = 1000 Whole-cell recording Tracheal smooth muscle Pig Yamakage et al. (1995)
(R,S)-KET IC50 = 9.2 Whole-cell recording Atrial myocytes Bullfrog Hatakeyama 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.