Hydroxynorketamine

Hydroxynorketamine
Systematic (IUPAC) name
2-Amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one
Identifiers
CAS Number 81395-70-2
ATC code None
PubChem CID 133669
ChemSpider 117907
Chemical data
Formula C12H14ClNO2
Molar mass 239.69806 g/mol

Hydroxynorketamine (HNK), or 6-hydroxynorketamine, is a metabolite of ketamine which is formed by hydroxylation of its metabolite norketamine.[1] In contrast to ketamine and norketamine, hydroxynorketamine is inactive as an anesthetic and psychostimulant.[2][3] In accordance, it has only very weak affinity for the NMDA receptor (Ki = 21.19 µM and > 100 μM for (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine, respectively).[4] However, hydroxynorketamine 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).[4] Moreover, (2S,6S)-hydroxynorketamine 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)-hydroxynorketamine, 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.[5][6][7] This finding has led to a call of reassessment of the understanding of the rapid antidepressant effects of ketamine and their mechanisms.[8] However, subsequent research has found that dehydronorketamine, which is a potent and select antagonist of the α7-nicotinic acetylcholine receptor similarly to hydroxynorketamine, 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.[9] This is likely due to the far lower potency of dehydronorketamine as an NMDA receptor antagonist in comparison.[9]

See also

References

  1. ↑ 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. Cite uses deprecated parameter |coauthors= (help)
  2. ↑ 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.
  3. ↑ 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.
  4. 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Hymie Anisman (6 May 2015). Stress and Your Health: From Vulnerability to Resilience. John Wiley & Sons. pp. 256–. ISBN 978-1-118-85028-2.
  8. ↑ 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.
  9. 1 2 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.


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