Desmethylclozapine
Desmethylclozapine
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Desmethylclozapine

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Desmethylclozapine

N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine.

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 muscarinic acetylcholine M1 receptor and the δ-opioid receptor, 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 of the M3 receptor, and a silent antagonist of the M4 receptor. It also binds with high affinity 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 trials found NMDC itself ineffective in the treatment of schizophrenia. 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 symptoms on its own, it cannot be ruled out that NDMC may contribute to the efficacy of clozapine on cognitive and/or negative symptoms.

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