''N''-Desmethylclozapine (NDMC), or norclozapine, is a major active

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of the atypical antipsychotic

drug A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...

clozapine. Unlike clozapine, it possesses intrinsic activity at the D₂/ D₃ receptors, and acts as a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonistic e ...

at these sites similarly to aripiprazole and

bifeprunox Bifeprunox (INN) (code name DU-127,090) is an atypical antipsychotic which, similarly to aripiprazole, combines minimal D2 receptor agonism with serotonin receptor agonism. It was under development for the treatment of schizophrenia but has sinc ...

. Notably, NDMC has also been shown to act as a potent and

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

at the M₁ and

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous ligan ...

s, unlike clozapine as well. It was hypothesized that on account of these unique actions, NDMC might underlie the clinical superiority of clozapine over other antipsychotics. However,

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s found NMDC itself ''ineffective'' in the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

. This may be because it possesses relatively low D₂/D₃ occupancy compared to 5-HT₂ (<15% versus 64-79% at a dose of 10–60 mg/kg s.c. in animal studies). Albeit not useful in the treatment of

positive symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

s on its own, it cannot be ruled out that NDMC may contribute to the efficacy of clozapine on

cognitive Cognition refers to "the mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

and/or

negative symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

References

Antipsychotics Chloroarenes Delta-opioid receptor agonists Dibenzodiazepines Mu-opioid receptor agonists Muscarinic agonists Piperazines Human drug metabolites {{Analgesic-stub

See also

References