Norketamine

Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4.[1][2] Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist (Ki = 1.7 μM and 13 μM for (S)-(+)-norketamine and (R)-(–)-norketamine, respectively),[1][3] but is about 3–5 times less potent as an anesthetic in comparison.[2][4] Also, similarly again to ketamine, norketamine binds to the μ- and κ-opioid receptors.[5] Relative to ketamine, norketamine is much more potent as an antagonist of the α7-nicotinic acetylcholine receptor, and produces rapid antidepressant effects in animal models which have been reported to correlate with its activity at this receptor.[6] However, norketamine is about 1/5 as potent as ketamine as an antidepressant in mice as per the forced swim test, and this seems also to be in accordance with its 3–5-fold reduced comparative potency in vivo as an NMDA receptor antagonist.[7] Norketamine is metabolized into dehydronorketamine and hydroxynorketamine, which are far less or negligibly active as NMDA receptor antagonists in comparison,[2] but retain activity as potent antagonists of the α7-nicotinic acetylcholine receptor.[8][9]

Norketamine
Clinical data
ATC code
  • None
Legal status
Legal status
Identifiers
  • 2-Amino-2-(2-chlorophenyl)cyclohexan-1-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC12H14ClNO
Molar mass223.70 g·mol−1
3D model (JSmol)
  • C1CCC(C(=O)C1)(C2=CC=CC=C2Cl)N
  • InChI=1S/C12H14ClNO/c13-10-6-2-1-5-9(10)12(14)8-4-3-7-11(12)15/h1-2,5-6H,3-4,7-8,14H2
  • Key:BEQZHFIKTBVCAU-UHFFFAOYSA-N

References
  1. Adams AP, Cashman JN, Grounds RM (12 January 2002). Recent Advances in Anaesthesia and Intensive Care. Cambridge University Press. pp. 42–. ISBN 978-1-84110-117-0.
  2. Barceloux DG (3 February 2012). Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. John Wiley & Sons. pp. 112–. ISBN 978-1-118-10605-1.
  3. Smith HS (21 December 2008). Current Therapy in Pain. Elsevier Health Sciences. pp. 482–. ISBN 978-1-4377-1117-2.
  4. Stanley TH, Schafer PG (6 December 2012). Pediatric and Obstetrical Anesthesia: Papers presented at the 40th Annual Postgraduate Course in Anesthesiology, February 1995. Springer Science & Business Media. pp. 372–. ISBN 978-94-011-0319-0.
  5. Smith BP (21 April 2014). Large Animal Internal Medicine. Elsevier Health Sciences. pp. 30–. ISBN 978-0-323-08840-4.
  6. 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.
  7. 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.
  8. 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.
  9. Lester RA (11 November 2014). Nicotinic Receptors. Springer. pp. 445–. ISBN 978-1-4939-1167-7.
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