Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of the

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens that distort perception of sight and sound and produce feelings of detachment – dissociation – from the environment and/or self. Although many kinds of drugs are capable of ...

, and

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

. It is formed by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

of the intermediate

norketamine Norketamine, or ''N''-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as ...

, another metabolite of ketamine. As of late 2019, (2''R'',6''R'')-HNK is in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s for the treatment of depression. The major metabolite of ketamine is norketamine (80%). Norketamine is secondarily converted into 4-, 5-, and 6-hydroxynorketamines (15%), mainly HNK (6-hydroxynorketamine). Ketamine is also transformed into hydroxyketamine (5%). As such, bioactivated HNK comprises less than 15% of a dose of ketamine.

Pharmacology

In contrast to ketamine and norketamine, HNK is inactive as an

and

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

. In accordance, it has only very weak

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the

NMDA receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other ...

(K_i = 21.19 μM and > 100 μM for (2''S'',6''S'')-HNK and (2''R'',6''R'')-HNK, respectively). However, HNK does still show

biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...

, having been found to act as a potent and selective

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...

of the α₇-nicotinic acetylcholine receptor ( IC₅₀ < 1 μM). Moreover, (2''S'',6''S'')-HNK was tested and found to increase the function of the

mammalian target of rapamycin The mammalian target of sirolimus, rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the ''M ...

(mTOR), a marker of the

activity of ketamine, far more potently than ketamine itself (0.05 nM for (2''S'',6''S'')-HNK, 10 nM for (''S'')-norketamine, and 1,000 nM for (''S'')-ketamine (

esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

), respectively), an action that was observed to correlate closely with their ability to inhibit the α₇-nicotinic acetylcholine receptor. This finding has led to a call of reassessment of the understanding of the rapid antidepressant effects of ketamine and their mechanisms. However, subsequent research has found that

dehydronorketamine Dehydronorketamine (DHNK), or 5,6-dehydronorketamine, is a minor metabolite of ketamine which is formed by dehydrogenation of its metabolite norketamine. Though originally considered to be inactive, DHNK has been found to act as a potent and sele ...

, which is a potent and selective

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.forced swim test ''Forced'' is a single-player and co-op action role-playing game developed by BetaDwarf, released in October 2013 for Windows, OS X and Linux through the Steam platform as well as Wii U. It is about gladiators fighting for their freedom in a fant ...

at doses up to 50 mg/kg in mice, and this is in contrast to ketamine and norketamine, which are effective at doses of 10 mg/kg and 50 mg/kg, respectively. In May 2016, a study published in the journal ''

Nature Nature is an inherent character or constitution, particularly of the Ecosphere (planetary), ecosphere or the universe as a whole. In this general sense nature refers to the Scientific law, laws, elements and phenomenon, phenomena of the physic ...

'' determined that HNK, specifically (2''S'',6''S'';2''R'',6''R'')-HNK, is responsible for the antidepressant-like effects of ketamine in mice; administration of (2''R'',6''R'')-HNK demonstrated ketamine-type antidepressant-like effects, and preventing the metabolic conversion of ketamine into HNK blocked the antidepressant-like effects of the parent compound.NIH/National Institute of Mental Health. (2016, May 4)
Ketamine lifts depression via a byproduct of its metabolism: Team finds rapid-acting, non-addicting agent in mouse study
ScienceDaily. Retrieved May 7, 2016 As (2''R'',6''R'')-HNK, unlike ketamine, does not antagonize the NMDA receptor to a clinically relevant degree, and produces no dissociative or euphoric effects, it has consequently been concluded that the antidepressant effects of ketamine may in fact not be mediated via the NMDA receptor. This is tentative, as confirmation that the findings translate to humans is still needed, but it is notable that published human data show a positive association between the antidepressant responses of ketamine and plasma (2''S'',6''S'';2''R'',6''R'')-HNK levels. In accordance with the notion that the NMDA receptor is not responsible for the antidepressant effects of ketamine,

dizocilpine Dizocilpine ( INN), also known as MK-801, is a pore blocker of the NMDA receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is normally blocked with a ma ...

(MK-801), which binds to and blocks the same site on the NMDA receptor that ketamine does, lacks antidepressant-like effects. Moreover, the findings would explain why other NMDA receptor antagonists such as

memantine Memantine, sold under the brand name Namenda among others, is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is taken by mouth. Common side effects include headache, constipation, sleepiness, and dizz ...

lanicemine Lanicemine (AZD6765) is a low-trapping NMDA receptor antagonist that was under drug development, development by AstraZeneca for the management of severe and treatment-resistant depression. Lanicemine differs from ketamine in that it is a ''low- ...

, and traxoprodil have thus far failed to demonstrate ketamine-like antidepressant effects in human clinical trials. Instead of acting via blockade of the NMDA receptor, (2''R'',6''R'')-HNK increases activation of the

AMPA receptor The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic receptor, ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitator ...

via a currently unknown/uncertain mechanism. The compound is now under active investigation by researchers at NIMH for potential clinical use, and it is hoped that use of HNK instead will mitigate the various concerns (such as abuse and dissociation) of using ketamine itself in the treatment of depression. However, a June 2017 study found that (2''R'',6''R'')-HNK ''does'' in fact block the NMDA receptor, similarly to ketamine. These findings suggest that the antidepressant-like effects of (2''R'',6''R'')-HNK may not actually be NMDA receptor-independent and that it may act in a similar manner to ketamine. Ketamine, (2''R'',6''R'')-HNK, and (2''S'',6''S'')-HNK have been found to be possible

ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...

of the

estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...

ERα Estrogen receptor alpha (ERα), also known as NR3A1 (nuclear receptor subfamily 3, group A, member 1), is one of two main types of estrogen receptor, a nuclear receptor (mainly found as a chromatin-binding protein) that is activated by the se ...

(IC₅₀ = 2.31, 3.40, and 3.53 μM, respectively). In 2024, HNK was found to act as a highly potent

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s, including of the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

(MOR). It shares this action with ketamine and

. They are all active in this action at very low concentrations, for instance 1nM. Ketamine, norketamine, and HNK can potentiate the effects of

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

s like

met-enkephalin Met-enkephalin, also known as metenkefalin ( INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkep ...

and

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

opioids like

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

. Opioid receptor positive allosteric modulation by these agents may be involved in their therapeutic effects, for instance their

and

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects.

Research

(2''R'',6''R'')-HNK is under development by the

National Institute of Mental Health The National Institute of Mental Health (NIMH) is one of 27 institutes and centers that make up the National Institutes of Health (NIH). The NIH, in turn, is an agency of the United States Department of Health and Human Services and is the primar ...

(NIMH) in the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

for the treatment of depression. As of late 2019, it is in phase I

s for this indication. It is also under development under the developmental code name SPL-801-B by Cybin for depressive disorders.

References

{{Opioid receptor modulators 2-Chlorophenyl compounds Acyloins Analgesics Antidepressants Arylcyclohexylamines Drugs with unknown mechanisms of action Experimental drugs Experimental non-hallucinogens Human drug metabolites Nicotinic antagonists NMDA receptor antagonists Opioid modulators Opioid receptor positive allosteric modulators

Pharmacology

Research

See also

References