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

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ...

, which is formed mainly by CYP3A4. Similarly to ketamine, norketamine acts as a noncompetitive

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

(K_i = 1.7 μM and 13 μM for (''S'')-(+)-norketamine and (''R'')-(–)-norketamine, respectively), 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 two ...

in comparison. 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, 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 related receptors that bind op ...

s. Relative to ketamine, norketamine is much more potent as an antagonist of the α₇-nicotinic acetylcholine receptor, and produces rapid antidepressant 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, and ...

'' as an NMDA receptor antagonist. Norketamine is metabolized into dehydronorketamine and hydroxynorketamine, which are far less or negligibly active as NMDA receptor antagonists in comparison, but retain activity as potent antagonists of the α₇-nicotinic acetylcholine receptor.

References

Arylcyclohexylamines Antidepressants Chloroarenes Dissociative drugs General anesthetics Human drug metabolites Kappa-opioid receptor agonists Ketones Mu-opioid receptor agonists Nicotinic antagonists NMDA receptor antagonists Sedatives {{Analgesic-stub