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| Routes of administration | Oral |
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| ECHA InfoCard | 100.164.220 |
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| Formula | C17H17ClN4 |
| Molar mass | 312.80 g·mol−1 |
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N-Desmethylclozapine (NDMC), ornorclozapine, is a majoractivemetabolite of theatypical antipsychoticdrugclozapine.[1][2]
Unlike clozapine, it possessesintrinsic activity at theD2/D3 receptors, and acts as a weakpartial agonist at these sites similarly toaripiprazole andbifeprunox.[3] Notably, NDMC has also been shown to act as apotent andefficaciousagonist at themuscarinic acetylcholineM1 receptor and theδ-opioid receptor, unlike clozapine as well.[4][5][6] It is a moderate-efficacy partial agonist of the muscarinic acetylcholine M1 andM2 receptors, a very weak partial agonist orantagonist of theM3 receptor, and asilent antagonist of theM4 receptor.[7] It also binds with highaffinity to theM5 receptor, but its intrinsic activity was not reported for this receptor.[7]
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 ofschizophrenia.[8][9] This may be because it possesses relatively low D2/D3 occupancy compared to the5-HT2 receptor (<15% versus 64–79% at a dose of 10–60 mg/kgs.c. in animal studies).[10]
Albeit not useful in the treatment ofpositive symptoms on its own, it cannot be ruled out that NDMC may contribute to the efficacy of clozapine oncognitive and/ornegative symptoms.[8]