Hydroxynorketamine

Hydroxynorketamine
(2R,6R)-Hydroxynorketamine
(2S,6S)-Hydroxynorketamine
The four possible stereoisomers of Hydroxynorketamine
(2R,6S)-Hydroxynorketamine (2S,6R)-Hydroxynorketamine
Clinical data
Other namesHNK; 6-Hydroxynorketamine; 6-HNK
ATC code
  • None
Identifiers
IUPAC name
  • 2-Amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H14ClNO2
Molar mass239.70 g·mol−1
3D model (JSmol)
SMILES
  • C1CC(C(=O)C(C1)(C2=CC=CC=C2Cl)N)O
InChI
  • 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]

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, 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.[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

References

  1. 1 2 Ronald D. Miller; Lars I. Eriksson; Lee A Fleisher; Jeanine P. Wiener-Kronish; William L. Young (24 June 2009). Anesthesia. Elsevier Health Sciences. pp. 743–. ISBN 978-1-4377-2061-7.
  2. 1 2 3 Hashimoto, Kenji (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. ISSN 1323-1316. PMC 6851782. PMID 31215725.
  3. 1 2 3 4 Mion, Georges; Villevieille, Thierry (2013). "Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings)". CNS Neuroscience & Therapeutics. 19 (6): 370–380. doi:10.1111/cns.12099. ISSN 1755-5930. PMC 6493357. PMID 23575437.
  4. ↑ Leung, Louis Y.; Baillie, Thomas A. (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. ISSN 0022-2623. PMID 3783598.
  5. ↑ Wainer, Irving W. (2014). "Are basal D-serine plasma levels a predictive biomarker for the rapid antidepressant effects of ketamineand ketamine metabolites?". Psychopharmacology. 231 (20): 4083–4084. doi:10.1007/s00213-014-3736-6. ISSN 0033-3158. PMID 25209678. S2CID 38125308.
  6. 1 2 Moaddel, Ruin; Abdrakhmanova, Galia; Kozak, Joanna; Jozwiak, Krzysztof; Toll, Lawrence; Jimenez, Lucita; Rosenberg, Avraham; Tran, Thao; Xiao, Yingxian; Zarate, Carlos A.; Wainer, Irving W. (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. ISSN 0014-2999. PMC 3534778. PMID 23183107.
  7. ↑ Paul, Rajib K.; Singh, Nagendra S.; Khadeer, Mohammed; Moaddel, Ruin; Sanghvi, Mitesh; Green, Carol E.; O’Loughlin, Kathleen; Torjman, Marc C.; Bernier, Michel; Wainer, Irving W. (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. ISSN 0003-3022. PMC 4061505. PMID 24936922.
  8. ↑ van Velzen, Monique; Dahan, Albert (2014). "Ketamine Metabolomics in the Treatment of Major Depression". Anesthesiology. 121 (1): 4–5. doi:10.1097/ALN.0000000000000286. ISSN 0003-3022. PMID 24936919.
  9. ↑ Hymie Anisman (6 May 2015). Stress and Your Health: From Vulnerability to Resilience. John Wiley & Sons. pp. 256–. ISBN 978-1-118-85028-2.
  10. 1 2 Singh, Nagendra S; Zarate, Carlos A; Moaddel, Ruin; Bernier, Michel; Wainer, Irving W (2014). "What is hydroxynorketamine and what can it bring to neurotherapeutics?". Expert Review of Neurotherapeutics. 14 (11): 1239–1242. doi:10.1586/14737175.2014.971760. ISSN 1473-7175. PMC 5990010. PMID 25331415.
  11. ↑ Sałat K, Siwek A, Starowicz G, Librowski T, Nowak G, Drabik U, Gajdosz R, Popik P (2015). "Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: Role of activity at NMDA receptor". Neuropharmacology. 99: 301–7. doi:10.1016/j.neuropharm.2015.07.037. PMID 26240948. S2CID 19880543.
  12. 1 2 3 4 5 6 7 Zanos, Panos; Moaddel, Ruin; Morris, Patrick J.; Georgiou, Polymnia; Fischell, Jonathan; Elmer, Greg I.; Alkondon, Manickavasagom; Yuan, Peixiong; Pribut, Heather J.; Singh, Nagendra S.; Dossou, Katina S. S.; Fang, Yuhong; Huang, Xi-Ping; Mayo, Cheryl L.; Wainer, Irving W.; Albuquerque, Edson X.; Thompson, Scott M.; Thomas, Craig J.; Zarate Jr, Carlos A.; Gould, Todd D. (2016). "NMDAR inhibition-independent antidepressant actions of ketamine metabolites". Nature. 533 (7604): 481–486. Bibcode:2016Natur.533..481Z. doi:10.1038/nature17998. ISSN 0028-0836. 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
  14. ↑ Collins, Francis (2016-05-10). "Fighting Depression: Ketamine Metabolite May Offer Benefits Without the Risks". Director's Blog. National Institutes of Health. Retrieved 2016-05-14.
  15. ↑ Morris PJ, Moaddel R, Zanos P, Moore CE, Gould T, Zarate CA, Thomas CJ (2017). "Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites". Org. Lett. 19 (17): 4572–4575. doi:10.1021/acs.orglett.7b02177. PMC 5641405. PMID 28829612.
  16. 1 2 Suzuki K, Nosyreva E, Hunt KW, Kavalali ET, Monteggia LM (2017). "Effects of a ketamine metabolite on synaptic NMDAR function". Nature. 546 (7659): E1–E3. Bibcode:2017Natur.546E...1S. doi:10.1038/nature22084. PMID 28640258. S2CID 4384957.
  17. 1 2 Kavalali ET, Monteggia LM (2018). "The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects". Neuropsychopharmacology. 43 (1): 221–222. doi:10.1038/npp.2017.210. PMC 5719113. PMID 29192654.
  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". Biochem. Pharmacol. 152: 279–292. doi:10.1016/j.bcp.2018.03.032. PMC 5960634. PMID 29621538.
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