Hydroxynorketamines: Pharmacology and Potential Therapeutic Applications

Abstract

Hydroxynorketamines (HNKs) are formed in vivo after (R,S)-ketamine (ketamine) administration. The 12 HNK stereoisomers are distinguished by the position of cyclohexyl ring hydroxylation (at the 4, 5, or 6 position) and their unique stereochemistry at two stereocenters. Although HNKs were initially classified as inactive metabolites because of their lack of anesthetic effects, more recent studies have begun to reveal their biologic activities. In particular, (2R,6R)- and (2S 6)-HNK exert antidepressant-relevant behavioral and physiologic effects in preclinical models, which led to a rapid increase in studies seeking to clarify the mechanisms by which HNKs exert their pharmacological effects. To date, the majority of HNK research has focused on the actions of (2R,6R)-HNK because of its robust behavioral actions in tests of antidepressant effectiveness and its limited adverse effects. This review describes HNK pharmacokinetics and pharmacodynamics, as well as the putative cellular, molecular, and synaptic mechanisms thought to underlie their behavioral effects, both following their metabolism from ketamine and after direct administration in preclinical studies. Converging preclinical evidence indicates that HNKs modulate glutamatergic neurotransmission and downstream signaling pathways in several brain regions, including the hippocampus and prefrontal cortex. Effects on other neurotransmitter systems, as well as possible effects on neurotrophic and inflammatory processes, and energy metabolism, are also discussed. Additionally, the behavioral effects of HNKs and possible therapeutic applications are described, including the treatment of unipolar and bipolar depression, post-traumatic stress disorder, chronic pain, neuroinflammation, and other anti-inflammatory and analgesic uses. SIGNIFICANCE STATEMENT: Preclinical studies indicate that hydroxynorketamines (HNKs) exert antidepressant-relevant behavioral actions and may also have analgesic, anti-inflammatory, and other physiological effects that are relevant for the treatment of a variety of human diseases. This review details the pharmacokinetics and pharmacodynamics of the HNKs, as well as their behavioral actions, putative mechanisms of action, and potential therapeutic applications.

Conflict of interest statement

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.

U.S. Government work not protected by U.S. copyright.

Figures

Fig. 1.

Metabolic formation of hydroxynorketamines from ketamine. (R,S)-ketamine (KET) is N-demethylated to form (R,S)-norketamine (norKET), which is then further metabolized to form the HNKs and dehydronorketamine (DHNK). Via this pathway, (R,S)-norKET is hydroxylated to form the HNKs as shown [see Portmann et al. (2010); Desta et al. (2012)]. Ketamine additionally undergoes direct hydroxylation to form the 6-hydroxyketamines (HKs), which are then N-demethylated to form the (2,6)-HNKs (Portmann et al., 2010; Desta et al., 2012).

Fig. 2.

Putative synaptic mechanisms of (2R,6R)- and (2S,6S)-hydroxynorketamine. (2R,6R)- HNK acts on the presynaptic terminal to increase glutamate release, possibly via signaling mechanisms convergent with mGlu2, whereby (2R,6R)-HNK disinhibits the mGlu2-induced cAMP release, or via another glutamate release mechanism. Subsequent to enhanced glutamate release, AMPAR activation leads to enhanced BDNF release, TrkB activation, and subsequent activation of plasticity-relevant signal cascades, including an increase in protein kinase B (AKT), extracellular signal–related kinases (ERK)/mitogen-activated proteain kinases (MAPK), and mTORC1 pathway activity. These signaling cascades result in protein synthesis, including increased AMPAR expression, and synaptogenesis, ultimately promoting enhanced synaptic strength. (2R,6R)-HNK may also disrupt TrkB/AP-2 interactions, thereby inhibiting TrkB endocytosis and enhancing TrkB stability at the synapse. Additionally, (2S,6S)-HNK has moderate affinity to inhibit NMDARs and may act to increase intracellular signal cascades via an NMDAR inhibition–dependent pathway, including inhibition of eEF2 signaling in addition to increased AKT, ERK/MAPK, and mTORC1 signaling.