Desmethylclozapine
Encyclopedia
N-Desmethylclozapine or norclozapine, is a major active
metabolite
of the atypical antipsychotic
drug
clozapine
. Interestingly, unlike clozapine, it possesses intrinsic activity
at the D2/D3 receptors, and acts as a weak partial agonist
at these sites similarly to aripiprazole
and bifeprunox
. Notably, NDMC has also been shown to act as a potent
and efficacious
agonist
at the M1 and δ-opioid receptors, unlike clozapine as well. Therefore, NDMC is considered a delta-opioid agonist. It was hypothesized that on account of these unique actions, NDMC might underlie the clinical superiority of clozapine over other antipsychotics. However, clinical trial
s found NMDC itself ineffective in the treatment of schizophrenia
. 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). In any case, though not useful in the treatment of positive symptoms on its own, it cannot be ruled out that NDMC may contribute to the improvement of cognitive
and/or negative symptoms with clozapine.
Activity (chemistry)
In chemical thermodynamics, activity is a measure of the “effective concentration” of a species in a mixture, meaning that the species' chemical potential depends on the activity of a real solution in the same way that it would depend on concentration for an ideal solution.By convention, activity...
metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
of the atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
. Interestingly, unlike clozapine, it possesses intrinsic activity
Intrinsic activity
Intrinsic activity or efficacy refers 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 to its molecular target, and the EC50, which is a measure of the...
at the D2/D3 receptors, and acts as a weak partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
at these sites similarly to aripiprazole
Aripiprazole
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
and bifeprunox
Bifeprunox
Bifeprunox is a novel atypical antipsychotic agent which, along with SLV313, aripiprazole, and SSR-181507 combines minimal D2 receptor agonism with 5-HT receptor agonism....
. Notably, NDMC has also been shown to act as a potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
and efficacious
Intrinsic activity
Intrinsic activity or efficacy refers 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 to its molecular target, and the EC50, which is a measure of the...
agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
at the M1 and δ-opioid receptors, unlike clozapine as well. Therefore, NDMC is considered a delta-opioid agonist. 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 trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s found NMDC itself ineffective in the treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. 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.
Subcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
in animal studies). In any case, though not useful in the treatment of positive symptoms on its own, it cannot be ruled out that NDMC may contribute to the improvement of cognitive
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...
and/or negative symptoms with clozapine.