Hydroxynorketamine

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Hydroxynorketamine
(2R,6R)-Hydroxynorketamine Formula V1.svg
(2S,6S)-Hydroxynorketamine Formula V1.svg
The four possible stereoisomers of Hydroxynorketamine
(2R,6S)-Hydroxynorketamine Formula V1.svg (2S,6R)-Hydroxynorketamine Formula V1.svg
Clinical data
Other namesHNK; 6-Hydroxynorketamine; 6-HNK
ATC code
  • None
Identifiers
  • 2-Amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
Formula C12H14ClNO2
Molar mass 239.70 g·mol−1
3D model (JSmol)
  • C1CC(C(=O)C(C1)(C2=CC=CC=C2Cl)N)O
  • InChI=1S/C12H14ClNO2/c13-9-5-2-1-4-8(9)12(14)7-3-6-10(15)11(12)16/h1-2,4-5,10,15H,3,6-7,14H2
  • Key:CFBVGSWSOJBYGC-UHFFFAOYSA-N

Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a minor metabolite of the anesthetic, dissociative, and antidepressant drug ketamine. [1] It is formed by hydroxylation of the intermediate norketamine, another metabolite of ketamine. [1] As of late 2019, (2R,6R)-HNK is in clinical trials for the treatment of depression. [2]

Contents

The major metabolite of ketamine is norketamine (80%). [3] Norketamine is secondarily converted into 4-, 5-, and 6-hydroxynorketamines (15%), mainly HNK (6-hydroxynorketamine). [3] Ketamine is also transformed into hydroxyketamine (5%). [3] As such, bioactivated HNK comprises less than 15% of a dose of ketamine. [3]

Pharmacology

In contrast to ketamine and norketamine, HNK is inactive as an anesthetic and psychostimulant. [4] [5] In accordance, it has only very weak affinity for the NMDA receptor (Ki = 21.19 μM and > 100 μM for (2S,6S)-HNK and (2R,6R)-HNK, respectively). [6] However, HNK does still show biological activity, having been found to act as a potent and selective negative allosteric modulator of the α7-nicotinic acetylcholine receptor (IC50 < 1 μM). [6] Moreover, (2S,6S)-HNK was tested and was found to increase the function of the mammalian target of rapamycin (mTOR), a marker of the antidepressant activity of ketamine, far more potently than ketamine itself (0.05 nM for (2S,6S)-HNK, 10 nM for (S)-norketamine, and 1,000 nM for (S)-ketamine (esketamine), respectively), an action that was observed to correlate closely with their ability to inhibit the α7-nicotinic acetylcholine receptor. [7] [8] [9] This finding has led to a call of reassessment of the understanding of the rapid antidepressant effects of ketamine and their mechanisms. [10] 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 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. [11]

In May 2016, a study published in the journal Nature determined that HNK, specifically (2S,6S;2R,6R)-HNK, is responsible for the antidepressant-like effects of ketamine in mice; administration of (2R,6R)-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. [12] [13] As (2R,6R)-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. [12] [13] This is tentative, as confirmation that the findings translate to humans is still needed, [14] but it is notable that published human data show a positive association between the antidepressant responses of ketamine and plasma (2S,6S;2R,6R)-HNK levels. [12] [13] In accordance with the notion that the NMDA receptor is not responsible for the antidepressant effects of ketamine, dizocilpine (MK-801), which binds to and blocks the same site on the NMDA receptor that ketamine does, lacks antidepressant-like effects. [12] Moreover, the findings would explain why other NMDA receptor antagonists such as memantine, lanicemine, and traxoprodil have thus far failed to demonstrate ketamine-like antidepressant effects in human clinical trials. [12] Instead of acting via blockade of the NMDA receptor, (2R,6R)-HNK increases activation of the AMPA receptor via a currently unknown/uncertain mechanism. [10] [12] 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. [12] [13]

However, a June 2017 study found that (2R,6R)-HNK does in fact block the NMDA receptor, similarly to ketamine. [16] [17] These findings suggest that the antidepressant-like effects of (2R,6R)-HNK may not actually be NMDA receptor-independent and that it may act in a similar manner to ketamine. [16] [17]

Ketamine, (2R,6R)-HNK, and (2S,6S)-HNK have been found to be possible ligands of the estrogen receptor ERα (IC50 = 2.31, 3.40, and 3.53 μM, respectively). [18]

Clinical development

(2R,6R)-HNK is under development by the National Institute of Mental Health (NIMH) in the United States for the treatment of depression. [2] As of late 2019, it is in phase I clinical trials for this indication. [2]

See also

Related Research Articles

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Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression, a pain management tool, and as a recreational drug. Ketamine is a novel compound that was derived from phencyclidine in 1962, in pursuit of a safer anesthetic with fewer hallucinogenic effects.

<span class="mw-page-title-main">Phencyclidine</span> Dissociative hallucinogenic drug, mostly used recreationally

Phencyclidine or phenylcyclohexyl piperidine (PCP), also known as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior. As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected. It may also be mixed with cannabis or tobacco.

<span class="mw-page-title-main">Imipramine</span> Antidepressant

Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine may also be used off-label for nocturnal enuresis and chronic pain. Imipramine is taken by mouth.

<span class="mw-page-title-main">Dizocilpine</span> Chemical compound

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 normally blocked with a magnesium ion and requires depolarization of the neuron to remove the magnesium and allow the glutamate to open the channel, causing an influx of calcium, which then leads to subsequent depolarization. Dizocilpine binds inside the ion channel of the receptor at several of PCP's binding sites thus preventing the flow of ions, including calcium (Ca2+), through the channel. Dizocilpine blocks NMDA receptors in a use- and voltage-dependent manner, since the channel must open for the drug to bind inside it. The drug acts as a potent anti-convulsant and probably has dissociative anesthetic properties, but it is not used clinically for this purpose because of the discovery of brain lesions, called Olney's lesions (see below), in laboratory rats. Dizocilpine is also associated with a number of negative side effects, including cognitive disruption and psychotic-spectrum reactions. It inhibits the induction of long term potentiation and has been found to impair the acquisition of difficult, but not easy, learning tasks in rats and primates. Because of these effects of dizocilpine, the NMDA receptor pore blocker ketamine is used instead as a dissociative anesthetic in human medical procedures. While ketamine may also trigger temporary psychosis in certain individuals, its short half-life and lower potency make it a much safer clinical option. However, dizocilpine is the most frequently used uncompetitive NMDA receptor antagonist in animal models to mimic psychosis for experimental purposes.

<span class="mw-page-title-main">Dextromethorphan</span> Antitussive medication of the dissociative class

Dextromethorphan (DXM) is a cough suppressant in over-the-counter cold and cough medicines. It affects NMDA, glutamate-1, and sigma-1 receptors in the brain, all of which have been implicated in the pathophysiology of depression. In 2022, the FDA approved a formulation of it combined with bupropion named Auvelity to serve as a rapid acting antidepressant in patients with major depressive disorder. It is sold in syrup, instant release tablet, extended release tablet, spray, and lozenge forms.

<span class="mw-page-title-main">NMDA receptor antagonist</span> Class of anesthetics

NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for animals and humans; the state of anesthesia they induce is referred to as dissociative anesthesia.

<span class="mw-page-title-main">Esketamine</span> Dissociative medication

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 names Spravato, Ketanest, among others. Esketamine is the active enantiomer of ketamine in terms of NMDA receptor antagonism and is more potent than racemic ketamine.

<span class="mw-page-title-main">Alpha-7 nicotinic receptor</span>

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<span class="mw-page-title-main">Neramexane</span> Chemical compound

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<span class="mw-page-title-main">2-Methyl-6-(phenylethynyl)pyridine</span> Chemical compound

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<span class="mw-page-title-main">Coronaridine</span> Chemical compound

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<span class="mw-page-title-main">Arketamine</span> Chemical compound

Arketamine (developmental code names PCN-101, HR-071603), also known as (R)-ketamine or (R)-(−)-ketamine, is the (R)-(−) enantiomer of ketamine. Similarly to racemic ketamine and esketamine, the S(+) enantiomer of ketamine, arketamine is biologically active; however, it is less potent as an NMDA receptor antagonist and anesthetic and thus has never been approved or marketed for clinical use as an enantiopure drug. Arketamine is currently in clinical development as a novel antidepressant.

<span class="mw-page-title-main">Norketamine</span> Major active metabolite of ketamine

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 an anesthetic in comparison.

<span class="mw-page-title-main">Dehydronorketamine</span> Chemical compound

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 selective negative allosteric modulator of the α7-nicotinic acetylcholine receptor (IC50 = 55 nM). For this reason, similarly to hydroxynorketamine (HNK), it has been hypothesized that DHNK may have the capacity to produce rapid antidepressant effects. However, unlike ketamine, norketamine, and HNK, DHNK has been found to be inactive in the forced swim test (FST) in mice at doses up to 50 mg/kg. DHNK is inactive at the α3β4-nicotinic acetylcholine receptor (IC50 > 100 μM) and is only very weakly active at the NMDA receptor (Ki = 38.95 μM for (S)-(+)-DHNK). It can be detected 7–10 days after a modest dose of ketamine, and because of this, is useful in drug detection assays.

<span class="mw-page-title-main">Threohydrobupropion</span> Type of substituted amphetamine derivative

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References

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  4. ↑ Leung LY, Baillie TA (November 1986). "Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine". Journal of Medicinal Chemistry. 29 (11): 2396–2399. doi:10.1021/jm00161a043. PMID   3783598.
  5. ↑ Wainer IW (October 2014). "Are basal D-serine plasma levels a predictive biomarker for the rapid antidepressant effects of ketamine and ketamine metabolites?". Psychopharmacology. 231 (20): 4083–4084. doi:10.1007/s00213-014-3736-6. PMID   25209678. S2CID   38125308.
  6. 1 2 Moaddel R, Abdrakhmanova G, Kozak J, Jozwiak K, Toll L, Jimenez L, et al. (January 2013). "Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors". European Journal of Pharmacology. 698 (1–3): 228–234. doi:10.1016/j.ejphar.2012.11.023. PMC   3534778 . PMID   23183107.
  7. ↑ Paul RK, Singh NS, Khadeer M, Moaddel R, Sanghvi M, Green CE, et al. (July 2014). "(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function". Anesthesiology. 121 (1): 149–159. doi:10.1097/ALN.0000000000000285. PMC   4061505 . PMID   24936922.
  8. ↑ van Velzen M, Dahan A (July 2014). "Ketamine metabolomics in the treatment of major depression". Anesthesiology. 121 (1): 4–5. doi: 10.1097/ALN.0000000000000286 . PMID   24936919.
  9. ↑ Anisman H (6 May 2015). Stress and Your Health: From Vulnerability to Resilience. John Wiley & Sons. pp. 256–. ISBN   978-1-118-85028-2.
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  11. ↑ Sałat K, Siwek A, Starowicz G, Librowski T, Nowak G, Drabik U, et al. (December 2015). "Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor". Neuropharmacology. 99: 301–307. doi:10.1016/j.neuropharm.2015.07.037. PMID   26240948. S2CID   19880543.
  12. 1 2 3 4 5 6 7 Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, et al. (May 2016). "NMDAR inhibition-independent antidepressant actions of ketamine metabolites". Nature. 533 (7604): 481–486. Bibcode:2016Natur.533..481Z. doi:10.1038/nature17998. PMC   4922311 . PMID   27144355.
  13. 1 2 3 4 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
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  18. ↑ Ho MF, Correia C, Ingle JN, Kaddurah-Daouk R, Wang L, Kaufmann SH, Weinshilboum RM (June 2018). "Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression". Biochemical Pharmacology. 152: 279–292. doi:10.1016/j.bcp.2018.03.032. PMC   5960634 . PMID   29621538.
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