TABLE 2

NMDAR ligand binding and functional inhibition

Ketamine Ki and IC50 values are only reported from studies that compared the effects of ketamine to HNKs under similar experimental conditions.

CompoundAffinity/PotencyReferences
NMDAR binding affinity (MK-801 displacement)
 (R,S)-ketamineKi = 0.25–1.06 µMMoaddel et al. (2013); Morris et al. (2017)
 (2S,6S)-HNKKi = 7.34–21.19 µM
 (2R,6R)-HNKKi > 100 µM
 (2R,5R)-HNKKi > 100 µM
 (2S,5S)-HNKKi > 100 µM
 (2R,5S)-HNKKi > 100 µM
 (2S,5R)-HNKKi > 100 µM
 (2R,4R)-HNKKi > 100 µM
 (2S,4S)-HNKKi > 100 µM
 (2R,4S)-HNKKi > 100 µM
 (2S,4R)-HNKKi > 100 µM
 (2R,6R)-HNKKi > 10 µMZanos et al. (2016)
 (2S,6S)-HNKKi > 10 µM
Inhibition of NMDAR-mediated current amplitude, X. laevis oocytes
 GluN subunits1A/2A1A/2B1A/2C1A/2D
 (R,S)-ketamineIC50 = 3.3 µMIC50 = 0.9 µMIC50 = 1.7 µMIC50 = 2.4 µMDravid et al. (2007); Lumsden et al. (2019)
 (2R,6R)-HNKIC50 = 498 µMIC50 = 258 µMIC50 = 202 µMIC50 = 287 µM
 (2S,6S)-HNKIC50 = 43 µMIC50 = 21 µMIC50 = 15 µM13 µM
Inhibition of NMDAR-mediated current amplitude, HEK-293 cells
 GluN subunits1A/2A1A/2B
 (R,S)-ketamineIC50 = 0.8 µM at pH 6.8NDAbbott and Popescu (2020)
IC50 = 0.5 µM at pH 7.2
 (2R,6R)-HNKIC50 = 46 µM at pH 6.8IC50 = 39 µM at pH 6.8
IC50 = 46 µM at pH 7.2IC50 = 69 µM at pH 7.2
Inhibition of NMDAR-mediated fEPSP slope, SC-CA1 mouse hippocampal slices
 (R,S)-ketamineIC50 = 4.5 µMLumsden et al. (2019)
 (2R,6R)-HNKIC50 = 211.9 µM
 (2S,6S)-HNKIC50 = 47.2 µM
Inhibition of NMDAR-mediated mEPSC amplitude, CA1 neurons in rat hippocampal slices
 (R,S)-ketamineIC50 = 6.4 µMLumsden et al. (2019)
 (2R,6R)-HNKIC50 = 63.7 µM
Inhibition of NMDAR-mediated mEPSCs, primary mouse hippocampal neurons
 (R,S)-ketamine50 µM (∼90% inhibition)Suzuki et al. (2017)
 (2R,6R)-HNK50 µM (∼40% inhibition)
10 µM (no inhibition)
Inhibition of NMDA-induced whole-cell current charge
 (R,S)-ketamineIC50 = 45.9 µMLumsden et al. (2019)
 (2R,6R)-HNKIC50 > 1000 µM
 (2S,6S)-HNKIC50 > 1000 µM
Attenuation of NMDA-induced lethality in mice
 (R,S)-ketamineED50 = 6.4 mg/kg, i.p.Lumsden et al. (2019)
 (2R,6R)-HNKED50 = 227.8 mg/kg, i.p.
 (2S,6S)-HNKED50 = 18.6 mg/kg, i.p.

  • ND, not determined; SC-CA1, Schaffer collateral-CA1 hippocampal synapse.