Clozapine was discovered in 1958 by an anesthetist and now it is used for the treatment of schizophrenia. Although the exact mechanism of its action is unknown, the effect of clozapine on schizophrenia is associated with inhibition of dopamine D2 and serotonin 2A receptors.

ACP-104 or N-Desmethylclozapine (NDMC), or norclozapine is a major metabolite of clozapine, which was developed like a small molecule drug candidate by ACADIA for treatment schizophrenia. ACP-104 combines M1 muscarinic agonist, 5-HT2A inverse agonist, and D2 and D3 dopamine partial agonist in a single compound and, therefore, uniquely addresses what ACADIA believed are the three most promising target mechanisms for treating schizophrenia. Then drug was discontinued, because the study did not meet its primary endpoint of antipsychotic efficacy or any of the secondary endpoints. Neither dose of ACP-104 demonstrated improved efficacy as compared to placebo. The most common adverse events in the treatment arms relative to placebo were increased salivation, tachycardia, and dyspepsia, which were noted to be dose-related. There was no clinically significant decrease in neutrophil counts in the study drug arms.

Clozapine N-oxide is a phase 1 metabolite of antipsychotic drug clozapine, produced by oxidation of clozapine by CYP3A4. Clozapine N-oxide is inert with respect to a wide range of GPCRs. It was used a tool compound in the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert compound, however interpretation of experiments is confounded by the ability of clozapine-N-oxide to convert to clozapine upon administration. Clozapine N-oxide exhibits neuroprotective action by inhibiting of microglial NADPH oxidase.