Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

Abstract

The following authors declare competing financial interests: R.M. and C.A.Z. are listed as co-inventors on a patent for the use of (2R,6R)hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro-and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.M., C.T., C.A.Z., and T.G. are listed as co-inventors on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. R.M., P.M., C.A.Z., and C.T. have assigned their patent rights to the United States government but will share a percentage of any royalties that may be received by the government. P.Z. and T.G. have assigned their patent rights to the University of Maryland Baltimore but will share a percentage of any royalties that may be received by the University of Maryland Baltimore. T.D.G. has received research funding from Allergan and Roche Pharmaceuticals and has served as a consultant for FSV7, LLC, during the preceding 3 years. All other authors declare no competing interests.

(R,S)-ketamine and (2R,6R)-hydroxynorketamine differentially affect memory as a function of dosing frequency

“…We have previously reported that ( 2R,6R )-HNK promotes a rapid potentiation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated activity in the hippocampus by increasing the probability of glutamate release at Schaffer collateral synapses [ 37 ]. This is hypothesized to initiate a synaptogenic process that involves a delayed upregulation of synaptic AMPARs several hours later, possibly sustaining its antidepressant effects [ 1 , 38 ]. This process could occlude further potentiation of those synapses by learned experiences that also depend on AMPAR upregulation as an expression mechanism.…”

“…We hypothesized that repeated exposure to ketamine and ( 2R,6R )-HNK will improve cognitive function through a persistent potentiation of the hippocampal activity or other metaplastic processes that enhances the efficacy of synaptic transmission. As an initial test of this hypothesis, we assessed changes in explicit, implicit, and working memory performance—discrete cognitive domains that are of clinical and mechanistic relevance to these compounds’ proposed antidepressant mechanism of action [ 1 , 38 ]. By implementing a comprehensive experimental design that controls for an effect of age, sex, dosing frequency, and heterogeneity in the experimental outcome, we find that ketamine and ( 2R,6R )-HNK differentially affect memory as a function of dosing frequency.…”

A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

“…However, ketamine plays diverse roles in the glutamatergic pathway and other neurotransmitter systems, neurogenesis, inflammation, and even body–brain crosstalk. Furthermore, several studies have suggested the distinct roles of ketamine enantiomers ([ S ]-ketamine and [ R ]-ketamine) and their metabolites ([ 2R,6R ]-HNK and [ 2S,6S ]-HNK) in plasticity and behavior ( Zanos et al, 2016 ; Yamaguchi et al, 2018 ; Hashimoto, 2019 ; Lumsden et al, 2019 ; Yokoyama et al, 2020 ; Highland et al, 2021 ; Wei et al, 2021 ). Thus, mechanisms underlying ketamine’s actions remain controversial.…”

“…Recent preclinical data indicate that ketamine’s enantiomer ( R )-ketamine ( Hashimoto, 2019 ; Wei et al, 2021 ) and its metabolites ( 2R, 6R )-hydroxynorketamine (HNK) ( Zanos et al, 2016 ) exert antidepressant effects with fewer adverse effects than do ketamine or ( S )-ketamine. Since potential mechanisms underlying the rapid antidepressant actions of ketamine and its metabolites have been reviewed elsewhere ( Fukumoto et al, 2017 ; Yang C. et al, 2018 ; Duman et al, 2019 ; Krystal et al, 2019 ; Sial et al, 2020 ; Highland et al, 2021 ; Shinohara et al, 2021 ; Wei et al, 2021 ; Xia et al, 2021 ), we review the recent progress in deciphering mechanisms underlying ketamine’s sustained antidepressant effects, with a particular focus on the role of calcium signaling from a multiscale perspective.…”

Ketamine: Neuroprotective or Neurotoxic?

“…The two distinct cellular pathways described by the "disinhibition" and "direct inhibition" hypotheses may not be mutually exclusive, and the relative contributions of NMDARs in inhibitory and pyramidal neuron populations may vary by brain region and synapse types, as well developmental stage (Miller et al, 2015). Furthermore, the role of NMDARs in ketamine's mechanism of action more generally is unclear: Zanos et al (2016) reported that the metabolite (2R,6R)hydroxynorketamine possesses similar antidepressant effects but with substantially lower NMDAR affinity, and instead involves and early and sustained activation of α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptor (AMPARs) (Highland et al, 2021). While the NMDAR-independence of ketamine's antidepressant actions remains an ongoing debate (Collingridge et al, 2017;Suzuki et al, 2017;Zanos et al, 2017), clinical evaluations of HNK levels have also been explored (Highland et al, 2021): one study showed that higher levels of this ketamine metabolite in plasma are associated with less clinical improvement and suicidal thoughts (Grunebaum et al, 2019).…”