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 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]

In 2024, HNK was found to act as a highly potent positive allosteric modulator of the opioid receptors, including of the μ-opioid receptor (MOR). [19] It shares this action with ketamine and norketamine. [19] They are all active in this action at very low concentrations, for instance 1 nM. [19] Ketamine, norketamine, and HNK can potentiate the effects of endogenous opioids like met-enkephalin and exogenous opioids like morphine. [19] Opioid receptor positive allosteric modulation by these agents may be involved in their therapeutic effects, for instance their antidepressant and analgesic effects. [19]

Research

(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] It is also under development under the developmental code name SPL-801-B by Cybin for depressive disorders. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Ketamine</span> Dissociative anesthetic and anti-depressant

Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a treatment for depression and in pain management. Ketamine is an NMDA receptor antagonist which accounts for most of its psychoactive effects.

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

Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug 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">Tramadol</span> Opioid pain medication

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with paracetamol (acetaminophen).

<span class="mw-page-title-main">Galantamine</span> Neurological medication

Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis, Galanthus caucasicus, Galanthus woronowii, and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata. It can also be produced synthetically.

<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 humans and animals; the state of anesthesia they induce is referred to as dissociative anesthesia.

δ-opioid receptor Opioid receptor

The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligands. The regions of the brain where the δ-opioid receptor is largely expressed vary from species model to species model. In humans, the δ-opioid receptor is most heavily expressed in the basal ganglia and neocortical regions of the brain.

<span class="mw-page-title-main">Alpha-7 nicotinic receptor</span> Type of cell receptor found in humans

The alpha-7 nicotinic receptor, also known as the α7 receptor, is a type of nicotinic acetylcholine receptor implicated in long-term memory, consisting entirely of α7 subunits. As with other nicotinic acetylcholine receptors, functional α7 receptors are pentameric [i.e., (α7)5 stoichiometry].

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

2-Methyl-6-(phenylethynyl)pyridine (MPEP) is a research drug which was one of the first compounds found to act as a selective antagonist for the metabotropic glutamate receptor subtype mGluR5. After being originally patented as a liquid crystal for LCDs, it was developed by the pharmaceutical company Novartis in the late 1990s. It was found to produce neuroprotective effects following acute brain injury in animal studies, although it was unclear whether these results were purely from mGluR5 blockade as it also acts as a weak NMDA antagonist, and as a positive allosteric modulator of another subtype mGlu4, and there is also evidence for a functional interaction between mGluR5 and NMDA receptors in the same populations of neurons. It was also shown to produce antidepressant and anxiolytic effects in animals, and to reduce the effects of morphine withdrawal, most likely due to direct interaction between mGluR5 and the μ-opioid receptor.

<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">Dextromethorphan/bupropion</span> Combination medication

Dextromethorphan/bupropion (DXM/BUP), sold under the brand name Auvelity, is a combination medication for the treatment of major depressive disorder (MDD). Its active components are dextromethorphan (DXM) and bupropion. Patients who stayed on the medication had an average of 11% greater reduction in depressive symptoms than placebo in an FDA approval trial. It is taken as a tablet by mouth.

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

Tulrampator is a positive allosteric modulator (PAM) of the AMPA receptor (AMPAR), an ionotropic glutamate receptor, which is under development by RespireRx Pharmaceuticals and Servier for the treatment of major depressive disorder, Alzheimer's disease, dementia, and mild cognitive impairment. Tulrampator was in phase II clinical trial for depression, but failed to show superiority over placebo. There are also phase II clinical trials for Alzheimer's disease and phase I trials for dementia and mild cognitive impairment.

<span class="mw-page-title-main">Erythrohydrobupropion</span> Substituted amphetamine derivative

Erythrohydrobupropion is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a minor active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities. Erythrohydrobupropion exists as a racemic mixture of two stereoisomers, (1R,2S)-erythrohydrobupropion and (1S,2R)-erythrohydrobupropion. Other metabolites of bupropion include hydroxybupropion and threohydrobupropion.

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

Threohydrobupropion is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities.

<span class="mw-page-title-main">Osavampator</span> Experimental antidepressant

Osavampator is an experimental drug being investigated as a treatment for treatment-resistant depression. It is being developed by Takeda Pharmaceuticals.

(2<i>R</i>,3<i>R</i>)-Hydroxybupropion Major metabolite of the antidepressant bupropion

(2R,3R)-Hydroxybupropion, or simply (R,R)-hydroxybupropion, is the major metabolite of the antidepressant, smoking cessation, and appetite suppressant medication bupropion. It is the (2R,3R)-enantiomer of hydroxybupropion, which in humans occurs as a mixture of (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion (radafaxine). Hydroxybupropion is formed from bupropion mainly by the cytochrome P450 enzyme CYP2B6. Levels of (2R,3R)-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy.

<span class="mw-page-title-main">BMS‐986122</span> Chemical compound

BMS‐986122 is a selective positive allosteric modulator (PAM) of the μ-opioid receptor (MOR).

References

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  2. 1 2 3 Hashimoto K (October 2019). "Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective". Psychiatry and Clinical Neurosciences. 73 (10): 613–627. doi:10.1111/pcn.12902. PMC   6851782 . PMID   31215725.
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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.
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  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.
  19. 1 2 3 4 5 Gomes I, Gupta A, Margolis EB, Fricker LD, Devi LA (August 2024). "Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors". Mol Pharmacol. doi:10.1124/molpharm.124.000947. PMID   39187388.
  20. ↑ "SPL 801 B (2R,6R-hydroxynorketamine (6-HNK))". AdisInsight. 23 October 2023. Retrieved 27 September 2024.
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