Desmethylclozapine

 ( 1-piperazinyl Compounds ) 

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, 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.

• Clozapine
• DHA-clozapine
• Loxapine