N-Desmethylclozapine (NDMC), or norclozapine, is a major active metabolite of the atypical antipsychotic drug clozapine.
Unlike clozapine, it possesses intrinsic activity at the D<sub>2</sub>/D<sub>3</sub> 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 M<sub>1</sub> receptor and the ô-opioid receptor, unlike clozapine as well. It is a moderate-efficacy partial agonist of the muscarinic acetylcholine M<sub>1</sub> and M<sub>2</sub> receptors, a very weak partial agonist or antagonist of the M<sub>3</sub> receptor, and a silent antagonist of the M<sub>4</sub> receptor. It also binds with high affinity to the M<sub>5</sub> 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 D<sub>2</sub>/D<sub>3</sub> occupancy compared to the 5-HT<sub>2</sub> receptor (<15% versus 64âÂÂ79% at a dose of 10âÂÂ60 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.