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	K_i = 0.49 ± 0.05	RBA—[³H]MK-801 binding	Cerebral cortex	Rat	Wong et al. (1986)
				K_i = 1.09	RBA—[³H]MK-801 binding	Brain	Rat	Wong et al. (1988)
				K_i = 1.09	RBA—[³H]MK-801 binding	Brain	Rat	Wong et al. (1988)
				K_i = 1.93	RBA—[³H]TCP binding	Brain	Rat	Wong et al. (1988)
				K_i = 0.42 ± 0.03	RBA—[³H]MK-801 binding	Cortex	Human	Kornhuber et al. (1989)
				K_i = 0.18 ± 0.03	RBA—[³H]MK-801 binding (no added glutamate or glycine)	Brain	Rat	Reynolds and Miller (1989)
				K_i = 0.24 ± 0.10	RBA—[³H]MK-801 binding (added 100 µM glutamate and 30 µM glycine)	Brain	Rat	Reynolds and Miller (1989)
				K_i = 0.58 ± 0.07	RBA—[³H]MK-801 binding	Brain	Mouse	Sharif et al. (1991)
				K_i = 0.76 ± 0.047	RBA—[³H]MK-801 binding	Brain	Guinea pig	Sharif et al. (1991)
				K_i = 0.48 ± 0.1	RBA—[³H]MK-801 binding	Brain	Dog	Sharif et al. (1991)
				K_i = 0.71 ± 0.06	RBA—[³H]MK-801 binding	Cortex	Dog	Sharif et al. (1991)
				K_i = 0.6 ± 0.04	RBA—[³H]MK-801 binding	Spinal cord	Rat	Sharif et al. (1991)
				K_i > 10	RBA—[³H]TCP binding	Rat glioma hybrid cells NG108-15	Rat	Georg and Friedl (1991)
				K_i = 1.19 ± 0.24	RBA—[³H]MK-801 binding	Cortex	Rat	Bresink et al. (1995)
				K_i = 0.20 ± 0.02	RBA—[³H]MK-801 binding	Brain (synaptic membranes)	Rat	Parsons et al. (1995)
				K_i = 1.0 ± 0.5	RBA—[¹²⁵I]MK-801 binding	Membranes from HEK293 cells transfected with GluN1/2A receptors	Rat	Lynch et al. (1995)
				K_i = 2.5 ± 1.2	RBA—[¹²⁵I]MK-801 binding	Membranes from HEK293 cells transfected with GluN1/2B receptors	Rat	Lynch et al. (1995)
				K_i = 2.51 ± 1.90	Autoradiographic binding—[³H]MK-801	Cerebellum	Rat	Bresink et al. (1995)
				K_i = 0.5 ± 0.15	RBA—[³H]MK-801 binding	Striatum	Rat	Kapur and Seeman (2001, 2002)
				K_i = 0.92	RBA—[³H]MK-801 binding	Brain membranes	Rat	Sun and Wessinger (2004)
				K_i = 3.1 ± 0.3	RBA—[³H]MK-801 binding	Striatum	Rat	Seeman et al. (2005)
				K_i = 1.35 ± 0.43	RBA—[³H]MK-801 binding	Cortex	Rat	Gilling et al. (2009)
				K_i = 0.67 ± 0.15	RBA—[³H]MK-801 binding	Cortex	Human	Gilling et al. (2009)
				K_i = 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)
				K_i = 0.32 ± 0.02	RBA—[³H]MK-801 binding	Forebrain	Rat	Wallach et al. (2016), Kang et al. (2017)
				K_i = 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		Rat receptors expressed in Xenopus oocytes
				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	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				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	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				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	K_i = 0.30 ± 0.013	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 0.69 ± 0.09	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 0.42 ± 0.04	RBA—[³H]MK-801 binding	Cortex	Pig	Bonifazi et al. (2015)
				K_i = 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	K_i = 1.40 ± 0.1	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 2.57 ± 0.28	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 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	K_i = 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		K_i = 1.7 ± 0.050	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 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		K_i = 13 ± 1.8	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 26.46	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 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	K_i = 38.95	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 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	K_i = 74.55	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 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	K_i = 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	K_i > 100	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i > 10	RBA—[³H]MK-801 binding	Whole brain	Rat	Zanos et al. (2016)
				K_i > 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	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ > 100
	(2S,6R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,6R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4R)-HNK	N/A	N/A	K_i > 100	RBA —[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4R)-HNK	N/A	N/A	IC₅₀ > 100	RBA —[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
D-serine	(S)-KET	Transport inhibitor	Antidepressant effects and dissociative side effects	EC₅₀ = 0.82 ± 0.29^{^a} (intracellular); 0.76 ± 0.13^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	PC-12 cells	Rat-derived cell line	Singh et al. (2015)
	(S)-KET	Transport inhibitor		EC₅₀ = 0.46 ± 0.25^{^a} (intracellular); 0.57 ± 0.32^{^a} (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 ± 0.16^{^a} (intracellular); 0.70 ± 0.10^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	PC-12 cells	Rat-derived cell line	Singh et al. (2015)
	(R)-KET			IC₅₀ = 0.75 ± 0.27^{^a} (intracellular); 0.88 ± 0.25^{^a} (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)	CE-LIF	1321N1 cells	Human-derived cell line	Singh et al. (2013)
	(2S,6S)-HNK			IC₅₀ = 0.00018 ± 0.00004^{^a} (intracellular)	CE-LIF	PC-12 cells	Rat-derived cell line	Singh et al. (2016c)
	(2R,6R)-HNK			IC₅₀ = 0.00068 ± 0.00009^{^a} (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)
HCN1	(S)-KET	Inhibitor	Anesthesia, antidepressant effects	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	K_i = 6.2 ± 1.1^{^a};	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)
GABA_AR	(R,S)-KET	Positive modulator	N/A	EC₅₀ = 1200 ± 600	Whole-cell recording	Human receptor expressed in HEK293 cells	Human	Flood and Krasowski (2000)
GABA_AR	(R,S)-KET	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	K_i = 45	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
M1 mAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 5.7	Two-microelectrode recording	Rat receptor expressed in Xenopus oocytes	Rat	Durieux (1995)
M2 mAChR	(R,S)-KET	N/R	N/A	K_i = 294	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
M3 mAChR	(R,S)-KET	N/R	N/A	K_i = 246	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
nAChR (muscle type)	(R,S)-KET	Antagonist	N/A	K_i = 16.5 ± 0.7^{^a} (resting); K_i = 13.1 ± 1.8^{^a} (desensitized)	RBA—[³H]TCP binding	AChR native membranes	T. californica	Arias et al. (2002)
		Antagonist		K_i = 20.9 ± 3.0^{^a}	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	K_i = 18.2 ± 1.2^{^a} (resting); K_i = 15.4 ± 2.3^{^a} (desensitized)	RBA—[³H]TCP binding	AChR native membranes	T. californica	Arias et al. (2002)
				K_i = 19.9 ± 2.8^{^a}	RBA—[³H]tetracaine binding	AChR native membranes	T. californica	Arias et al. (2002)
				K_i = 430 ± 330^{^a}	RBA—[¹⁴C]amobarbital binding	AChR native membranes	T. californica	Arias et al. (2002)
α nAChR	(R,S)-KET	Antagonist	N/A	EC₅₀ = 18.7 ± 7.4^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
α nAChR	(S)-KET	Antagonist		EC₅₀ = 9.7 ± 2.2^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
β nAChR	(R,S)-KET	Antagonist		EC₅₀ = 15.2 ± 3.6^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
β nAChR	(S)-KET	Antagonist		EC₅₀ = 7.4 ± 4.5^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
γ nAChR	(R,S)-KET	Antagonist		EC₅₀ = 20.4 ± 10.1^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
γ nAChR	(S)-KET	Antagonist		EC₅₀ = 6.6 ± 2.9^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
δ nAChR	(R,S)-KET	Antagonist		EC₅₀ = 19.4 ± 6.5^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
δ nAChR	(S)-KET	Antagonist		EC₅₀ = 8.5 ± 2.4^{^a}	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)
α4β4 nAChR	(R,S)-KET	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)
α4β2 nAChR	(R,S)-KET	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)
	(R,S)-KET	Antagonist		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)
	(R,S)-KET	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)
D_1–5R	(S)-KET	N/A	N/A	No functional effect up to 10 μM	RBA	Human receptor expressed in HEKT (for D_1/3/5R), 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	K_i = 1.0 ± 0.15	RBA	Striatum	Rat	Kapur and Seeman (2001, 2002)
				K_i = 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)
				K_i = 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)
	(R,S)-KET	Uptake inhibitor	N/A	K_i = 62.9 ± 2.3^{^a}	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	K_i = 15 ± 5	RBA	Frontal cortex	Rat	Kapur and Seeman (2002)
5-HT₃R	(R,S)-KET	Antagonist	N/A	K_i = 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	K_i = 420 ± 60	5-HT–induced currents: whole-cell recordings	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
5-HT₃R	(R,S)-KET	Noncompetitive antagonist	N/A	IC_50i = 910 ± 30	5-HT–induced currents: whole-cell recordings	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
5-HT_3AR	(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	K_i = 161.7 ± 28.3^{^a}	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	K_i = 66.8 ± 25.9^{^a}	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	K_i = 42.1	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 28.6	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 11	RBA—[³H]DAMGO	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 83.8	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 28	RBA—[³H]DAMGO	Whole brain	Rat	Hustveit et al. (1995)
κ opioid receptor	(R,S)-KET	Agonist		K_i = 28.1	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R,S)-KET	Agonist		K_i = 25.0; EC₅₀ = 29.0	RBA—[³⁵S]-GTPγS	Human receptor expressed in CHO cells	Human	Nemeth et al. (2010)
	(S)-KET	Agonist		K_i = 23.7	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 24	RBA—[³H]U69,593	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 60.0	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 100	RBA—[³H]U69,593	Whole brain	Rat	Hustveit et al. (1995)
δ opioid receptor	(R,S)-KET	Agonist		K_i = 272	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 205	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 130	RBA—[³H]DPDPE	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 286	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 130	RBA—[³H]DPDPE	Whole brain	Rat	Hustveit et al. (1995)
σ_1/2R	(R,S)-KET	N/R	Antidepressant effects	IC₅₀ = 66.0 ± 10.0	RBA – [³H] + SKF10,047	Spinal cord	Rat	Smith et al. (1987)
				K_i = 0.15	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
				K_i > 10	RBA—[³H]DTG	Rat glioma hybrid cells NG108-15	Rat	Georg and Friedl (1991)
	(R)-KET			K_i = 19	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
	(S)-KET			K_i = 131	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
σ₁R	(R,S)-KET			K_i = 139.60 ± 6.13	RBA—[³H] (+) pentazocine	Liver membrane	Rat	Robson et al. (2012)
σ₂R	(R,S)-KET			K_i = 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)
				K_i = 11.5	²²Na⁺-stimulated influx (measure sodium uptake)	Brain (minus cerebellum) synaptoneurosomal fractions	Rat	Allaoua and Chicheportiche (1989)
				ED₅₀ = 1100	Single channel recordings	Cortical synaptosome bilayer	Human	Frenkel and Urban (1992)
	(S)-KET	Antagonist		IC₅₀ = 240 ± 60^{^a} (neuronal), 59 ± 10^{^a} (skeletal)	Whole-cell recording	Rat channels expressed in HEK293 cells	Rat	Haeseler et al. (2003)
	(R)-KET	Antagonist		IC₅₀ = 333 ± 93^{^a} (neuronal), 181 ± 49^{^a} (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)
L-type VDCC	(R,S)-KET	Antagonist	Antidepressant effects	IC₅₀ = 9.2	Whole-cell recording	Atrial myocytes	Bullfrog	Hatakeyama et al. (2001)

CE-LIF, capillary electrophoresis-laser-induced fluorescence; D_1–5R, 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; GABA_AR, 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.