While most research has historically focused on its precursor, researchers have taken notice of norketamine's putative effects. Beginning in the late 1990s, Danish researchers discovered its role as a NMDA receptor antagonist. Later research uncovered its use as an antinociceptive, or "painkiller."
Much of the research examining the potential role of norketamine as a distinct anti-depressant to its precursor began in the mid-2010s. Rodent models have showcased that norketamine crosses the
blood-brain barrier, though considerably less efficiently than ketamine.[6] Accordingly, its antidepressant effects are less potent than enantiomers of ketamine, but appear to be as effective as
esketamine in its potency and duration.[7] Unlike esketamine, (S)-norketamine does not appear to significantly impact
prepulse inhibition (reduction of the startle reflex) and as such appears to have significantly fewer
psychotomimetic effects - which may indicate that it could be a safer alternative to ketamine for use as an antidepressant in humans.
Pharmacology
Pharmacodynamics
Similarly to ketamine, norketamine acts as a
noncompetitiveNMDA receptor antagonist (Ki = 1.7
μM and 13 μM for (S)-(+)-norketamine and (R)-(–)-norketamine, respectively). Also, similarly again to ketamine, norketamine binds to the
μ- and
κ-opioid receptors.[8] 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.[9] 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.[10] Norketamine's metabolites,
dehydronorketamine (DHNK) and
hydroxynorketamine (HNK), 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.[11][12]
Pharmacokinetics
Ketamine is effectively metabolized by the
superfamily of
cytochrome P450 enzymes, particularly CYP2B6 and CYP3A. Though these enzymes are predominantly found in the liver, they are present in many other organs and tissue groups throughout the body, localized to the
endoplasmic reticulum of such cells. Peak concentration of norketamine occurs roughly 17 minutes after initially administering ketamine. The subsequent metabolism of norketamine to hydroxynorketamine and dehydronorketamine from ketamine occurs 2–3 hours after ketamine infusion, and occurs at a roughly 30:70 formation ratio.[13] HNK is formed via the hydroxylation of the cyclohexone ring; these are then conjugated with
glucoronic acid to form DHNK.
As with their precursors ketamine and norketamine, HNK and DHNK are of great interest to pharmacologists for their putative anti-depressant and analgesic properties.
Chemistry
Synthesis
Stevens' original design utilized a continuous flow of bromine and ammonia, each highly toxic and corrosive reagents with considerable material compatibility issues.
^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.
PMID26240948.
S2CID19880543.
^Kamp J, Jonkman K, van Velzen M, Aarts L, Niesters M, Dahan A, Olofsen E (November 2020). "Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis". British Journal of Anaesthesia. 125 (5): 750–761.
doi:
10.1016/j.bja.2020.06.067.
hdl:1887/3182187.
PMID32838982.