Similarly to ketamine, norketamine acts as anoncompetitiveNMDA receptor antagonist (Ki = 1.7μM and 13μM for (S)-(+)-norketamine and (R)-(–)-norketamine, respectively). Also, similarly again to ketamine, norketamine binds to theμ- andκ-opioid receptors.[5] Relative to ketamine, norketamine is much more potent as anantagonist of theα7-nicotinic acetylcholine receptor, and produces rapidantidepressant effects inanimal 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 theforced swim test, and this seems also to be in accordance with its 3–5-fold reduced comparative potencyin vivo as an NMDA receptor antagonist.[7] Norketamine's metabolites,dehydronorketamine (DHNK) andhydroxynorketamine (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.[8][9]
Ketamine is effectively metabolized by thesuperfamily ofcytochrome 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 theendoplasmic 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.[11] HNK is formed via the hydroxylation of the cyclohexone ring; these are then conjugated withglucoronic 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.
Stevens' original design utilized a continuous flow of bromine and ammonia, each highly toxic and corrosive reagents with considerable material compatibility issues.
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 theblood-brain barrier, though considerably less efficiently than ketamine.[13] Accordingly, its antidepressant effects are less potent than enantiomers of ketamine, but appear to be as effective asesketamine in its potency and duration.[14] Unlike esketamine, (S)-norketamine does not appear to significantly impactprepulse inhibition (reduction of thestartle reflex) and as such appears to have significantly fewerpsychotomimetic effects - which may indicate that it could be a safer alternative to ketamine for use as an antidepressant in humans.
^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.
