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

dissociative Dissociatives, colloquially dissos, are a subclass of hallucinogens which 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 drug

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

. It is formed by hydroxylation 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 (Ki = 1.7 μM and 13 μM for (''S'')-(+ ...

, 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 participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

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. 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 Par ...

for the NMDA receptor (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, 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 stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

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

mammalian target of rapamycin The mammalian target of 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 ''MTOR'' gene. ...

(mTOR), a marker of the antidepressant 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, also known as (S)-ketamine or S(+)-ketamine, is the ''S''(+) enantiomer of ketamine, is a dissociative hallucinogen drug used as a general anesthetic and as an antidepressant for treatment of depression. It is sold under the brand n ...

), 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, which is a potent and selective antagonist of the α₇-nicotinic acetylcholine receptor similarly to HNK, is inactive in the

forced swim test The behavioural despair test (or Porsolt forced swimming test) is a test, centered on a rodent's response to the threat of drowning, whose result has been interpreted as measuring susceptibility to negative mood. It is commonly used to measure the ...

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, in the broadest sense, is the physical world or universe. "Nature" can refer to the phenomena of the physical world, and also to life in general. The study of nature is a large, if not the only, part of science. Although humans are ...

'' 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, is not an NMDA receptor antagonist, 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 ''N''-Methyl-D-aspartate (NMDA) receptor, a glutamate receptor, discovered by a team at Merck in 1982. Glutamate is the brain's primary excitatory neurotransmitter. The channel is ...

(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 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 dizziness. Severe side effects may include blood clots ...

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

, and

traxoprodil Traxoprodil (developmental code name CP-101606) is a drug developed by Pfizer which acts as an NMDA antagonist, selective for the NR2B subunit. It has neuroprotective, analgesic, and anti-Parkinsonian effects in animal studies. Traxoprodil has ...

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 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 of the

estrogen receptor Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol). Two classes of ER exist: nuclear estrogen receptors ( ERα and ERβ), which are members of the ...

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 sex h ...

(IC₅₀ = 2.31, 3.40, and 3.53 μM, respectively).

Clinical development

(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 prima ...

(NIMH) in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...

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

s for this indication.

References

{{Nicotinic acetylcholine receptor modulators Acyloins Antidepressants Arylcyclohexylamines Chloroarenes Drugs with unknown mechanisms of action Experimental drugs Human drug metabolites Nicotinic antagonists

Pharmacology

Clinical development

See also

References