Norketamine

Norketamine

Clinical data
ATC code	None
Legal status
Legal status	CA: Schedule I UK: Class B
Identifiers
IUPAC name 2-Amino-2-(2-chlorophenyl)cyclohexan-1-one
CAS Number	35211-10-0 79499-59-5 (HCl)
PubChem CID	123767
ChemSpider	110322
UNII	XQY6JVF94X
ChEMBL	ChEMBL1039
CompTox Dashboard (EPA)	DTXSID40891434
Chemical and physical data
Formula	C12H14ClNO
Molar mass	223.70 g·mol−1
3D model (JSmol)	Interactive image
SMILES C1CCC(C(=O)C1)(C2=CC=CC=C2Cl)N
InChI 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

Norketamine, or N-desmethylketamine, is the major active metabolite of ketamine, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive NMDA receptor antagonist, but is about 3–5 times less potent as an anesthetic in comparison.

History

Norketamine was synthesized by Calvin Lee Stevens in the early 1960s, as part of his team's work on α-aminoketones at Wayne State University.

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."

Following the 2019 approval of the ketamine enantiomer esketamine by the European Medicines Agency and FDA for use with treatment-resistant depression, researchers and pharmaceutical companies have sought other effective intermediates and metabolites of racemic ketamine.

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. Accordingly, its antidepressant effects are less potent than enantiomers of ketamine, but appear to be as effective as esketamine in its potency and duration. 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 psychomimetic 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 noncompetitive NMDA receptor antagonist (K_i = 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. 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. 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. Norketamine's metabolites, dehydronorketamine (DHNK) and hydroxynorketamine (HNK), are far less or negligibly active as NMDA receptor antagonists in comparison, but retain activity as potent antagonists of the α₇-nicotinic acetylcholine receptor.

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. 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.