Norketamine, or ''N''-desmethylketamine, is the major

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

ketamine Ketamine is a cyclohexanone-derived general anesthetic and NMDA receptor antagonist with analgesic and hallucinogenic properties, used medically for anesthesia, depression, and pain management. Ketamine exists as its S- (esketamine) a ...

, which is formed mainly by

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

. Similarly to ketamine, norketamine acts as a noncompetitive

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

, but is about 3–5 times less potent as an

anesthetic An anesthetic (American English) or anaesthetic (British English; see spelling differences) is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into t ...

in comparison.

Pharmacology

Pharmacodynamics

Similarly to ketamine, norketamine acts as a noncompetitive

(K_i = 1.7μM and 13μM for (''S'')-(+)-norketamine and (''R'')-(–)-norketamine, respectively). Also, similarly again to ketamine, norketamine binds to the μ- and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

s. Relative to ketamine, norketamine is much more potent as an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.α₇-nicotinic acetylcholine receptor, and produces rapid

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

effects in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' 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. In 2024, norketamine was discovered to act as a highly potent

positive allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that ...

of the

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s, including of the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

(MOR). It shares this action with ketamine and hydroxynorketamine (HNK). They are all active in this action at very low concentrations, for instance 1nM. Ketamine, norketamine, and HNK can potentiate the effects of

endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

s like

met-enkephalin Met-enkephalin, also known as metenkefalin ( INN), sometimes referred to as opioid growth factor (OGF), is a naturally occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkep ...

and

exogenous In a variety of contexts, exogeny or exogeneity () is the fact of an action or object originating externally. It is the opposite of endogeneity or endogeny, the fact of being influenced from within a system. Economics In an economic model, an ...

opioids like

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

. Opioid receptor positive allosteric modulation by these agents may be involved in their therapeutic effects, for instance their

and

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects.

Pharmacokinetics

Ketamine is effectively metabolized by the superfamily of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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 The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

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.

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 Wayne State University (WSU) is a public university, public research university in Detroit, Michigan, United States. Founded in 1868, Wayne State consists of 13 schools and colleges offering approximately 375 programs. It is Michigan's third-l ...

. 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 In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

esketamine Esketamine, sold under the brand names Spravato (for depression (mood), depression) and Ketanest (for anesthesia) among others, is the ''S''(+) enantiomer of ketamine. It is a dissociative hallucinogen drug used as a general anesthetic and as ...

by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

and

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

for use with

treatment-resistant depression Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Inad ...

, 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

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 psychotomimetic effects - which may indicate that it could be a safer alternative to ketamine for use as an antidepressant in humans.

References

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Pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

, titlestyle = background:#ccccff , list1 = {{Ionotropic glutamate receptor modulators {{Nicotinic acetylcholine receptor modulators {{Opioid receptor modulators 2-Chlorophenyl compounds Analgesics Antidepressants Arylcyclohexylamines Dissociative drugs General anesthetics Human drug metabolites Kappa-opioid receptor agonists Ketones Mu-opioid receptor agonists Nicotinic antagonists NMDA receptor antagonists Opioid modulators Sedatives Opioid receptor positive allosteric modulators