The four possible stereoisomers of Hydroxynorketamine
|Chemical and physical data|
|Molar mass||239.70 g/mol|
|3D model (Jmol)||Interactive image|
Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a metabolite of ketamine which is formed by hydroxylation of its metabolite norketamine. In contrast to ketamine and norketamine, HNK is inactive as an anesthetic and psychostimulant. 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). 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). 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. 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 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 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. 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. 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 (2S,6S;2R,6R)-HNK levels. 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. 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. Instead of acting via blockade of the NMDA receptor, (2R,6R)-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 is expected to mitigate the various concerns (such as abuse and dissociation) of using ketamine itself in 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.
- 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 1-4377-2061-7.
- 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.
- 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.
- 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.
- 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. PMID 24936922.
- 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.
- Hymie Anisman (6 May 2015). Stress and Your Health: From Vulnerability to Resilience. John Wiley & Sons. pp. 256–. ISBN 978-1-118-85028-2.
- 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. PMID 25331415.
- Sałat K, Siwek A, Starowicz G, Librowski T, Nowak G, Drabik U, et al. (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.
- 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. doi:10.1038/nature17998. ISSN 0028-0836.
- 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
- 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.
- 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.