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

active Active may refer to: Music * ''Active'' (album), a 1992 album by Casiopea * "Active" (song), a 2024 song by Asake and Travis Scott from Asake's album ''Lungu Boy'' * Active Records, a record label Ships * ''Active'' (ship), several com ...

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 The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as tranquilizers and neurol ...

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

clozapine Clozapine, sold under the brand name Clozaril among others, is a psychiatric medication and was the first atypical antipsychotic to be discovered. It is used primarily to treat people with schizophrenia and schizoaffective disorder who have ...

. Unlike clozapine, it possesses

intrinsic activity Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind ...

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 (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

at these sites similarly to

aripiprazole Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...

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, psychosis and ...

. 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 (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

at the muscarinic acetylcholine M₁ receptor and the

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 alpha subunit, Gi/G0 and has enkephalins as it ...

, unlike clozapine as well. It is a moderate-efficacy partial agonist of the muscarinic acetylcholine M₁ and M₂ receptors, a very weak partial agonist or

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.M₃ receptor, and a

silent antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the M₄ receptor. It also binds with high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

to the M₅ receptor, but its intrinsic activity was not reported for this receptor. It was hypothesized that on account of its 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 subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s found NMDC itself ineffective in the treatment of

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

. This may be because it possesses relatively low D₂/D₃ occupancy compared to the 5-HT₂ receptor (<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 Positive is a property of positivity and may refer to: Mathematics and science * Positive formula, a logical formula not containing negation * Positive number, a number that is greater than 0 * Plus sign, the sign "+" used to indicate a positi ...

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

cognitive Cognition is 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 diagnostic indications of an illness, injury, or condition. Signs are objective and externally observable; symptoms are a person's reported subjective experiences. A sign for example may be a higher or lower temperature ...

References

{{Tricyclics 1-Piperazinyl compounds Antipsychotics Chloroarenes Delta-opioid receptor agonists Dibenzodiazepines Human drug metabolites Mu-opioid receptor agonists M1 receptor agonists M2 receptor agonists M3 receptor agonists M3 receptor antagonists M4 receptor antagonists

See also

References