6104-71-8

Usage

Uses

Used in Pharmaceutical Industry:
N-Desmethylclozapine is used as a potent and selective 5-HT2C serotonin receptor antagonist for the treatment of schizophrenia. It plays a significant role in managing the symptoms of the disorder by targeting specific serotonin receptors in the brain.
Used in Clinical Research:
N-Desmethylclozapine is used as a standard to quantify the clozapine plasma levels in treatment-refractory Chinese schizophrenic patients. This application aids in understanding the drug's effectiveness and its impact on patients with schizophrenia.
Used in Urine Drug Testing:
N-Desmethylclozapine is utilized in urine drug testing, where it helps in detecting the presence of Clozapine or its metabolites in a patient's system. This application is crucial for clinical toxicology, forensic analysis, and clinical monitoring by LC-MS/MS or GC/MS.
Used in Clinical Toxicology:
In the field of clinical toxicology, N-Desmethylclozapine is employed to analyze and assess the potential toxic effects of Clozapine or its metabolites in a patient's body. This information is vital for determining the appropriate treatment and management strategies for patients undergoing Clozapine therapy.
Used in Forensic Analysis:
N-Desmethylclozapine plays a role in forensic analysis by helping to identify the presence of Clozapine or its metabolites in biological samples. This information can be crucial in legal investigations and cases involving the use of Clozapine or other related substances.

Biological Activity

A major metabolite of clozapine; a potent and selective 5-HT 2C serotonin receptor antagonist.

Biochem/physiol Actions

N-Desmethylclozapine serves as an agonist to muscarinic acetylcholine receptors, and is known to exert its antipsychotic action. It blocks synaptic transmission by antagonizing synaptic GABA (γ-aminobutyric acid) receptors.

InChI:InChI=1/C17H17ClN4/c18-12-5-6-15-16(11-12)21-17(22-9-7-19-8-10-22)13-3-1-2-4-14(13)20-15/h1-6,11,19,21H,7-10H2

Upstream product

• 110-85-0 piperazine 
• 50892-62-1 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one 
• 5786-21-0 clozaril 
• 50373-22-3 8,11-dichloro-5H-dibenzo[b,e][1,4]-diazepine 
• 118-92-3 anthranilic acid 
• 60091-87-4 2-(4-Chlor-2-nitrophenyl)aminobenzencarbonsaeure 
• 67990-66-3 N-(2-Amino-4-chlorophenyl)anthranilic acid 
• 41513-04-6 2-chloro-5-bromonitrobenzene 

Downstream Products

• 1179874-38-4 8-chloro-11-[4-(4-phenylbutyl)piperazino]-5H-dibenzo[b,e][1,4]diazepine 
• 1116338-63-6 C₃₂H₃₈ClN₅O 

Relevant academic research and scientific papers

Butyl methacrylate-co-ethylene glycol dimethacrylate monolith for online in-tube SPME-UHPLC-MS/MS to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples

This manuscript describes a sensitive, selective, and online in-tube solid-phase microextraction coupled with an ultrahigh performance liquid chromatography-tandem mass spectrometry (in-tube SPME-UHPLC-MS/MS) method to determine chlopromazine, clozapine, quetiapine, olanzapine, and their metabolites in plasma samples from schizophrenic patients. Organic poly(butyl methacrylate-co-ethylene glycol dimethacrylate) monolith was synthesized on the internal surface of a fused silica capillary (covalent bonds) for in-tube SPME. Analyte extraction and analysis was conducted by connecting the monolithic capillary to an UHPLC-MS/MS system. The monolith was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectrometry (FTIR). The developed method presented adequate linearity for all the target antipsychotics: R2 was higher than 0.9975, lack-of-fit ranged from 0.115 to 0.955, precision had variation coefficients lower than 14.2%, and accuracy had relative standard error values ranging from ?13.5% to 14.6%, with the exception of the lower limit of quantification (LLOQ). The LLOQ values in plasma samples were 10 ng mL?1 for all analytes. The developed method was successfully applied to determine antipsychotics and their metabolites in plasma samples from schizophrenic patients.

The first structure-activity relationship studies for designer receptors exclusively activated by designer drugs

Over the past decade, two independent technologies have emerged and been widely adopted by the neuroscience community for remotely controlling neuronal activity: optogenetics which utilize engineered channelrhodopsin and other opsins, and chemogenetics which utilize engineered G protein-coupled receptors (Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) and other orthologous ligand-receptor pairs. Using directed molecular evolution, two types of DREADDs derived from human muscarinic acetylcholine receptors have been developed: hM3Dq which activates neuronal firing, and hM4Di which inhibits neuronal firing. Importantly, these DREADDs were not activated by the native ligand acetylcholine (ACh), but selectively activated by clozapine N-oxide (CNO), a pharmacologically inert ligand. CNO has been used extensively in rodent models to activate DREADDs, and although CNO is not subject to significant metabolic transformation in mice, a small fraction of CNO is apparently metabolized to clozapine in humans and guinea pigs, lessening the translational potential of DREADDs. To effectively translate the DREADD technology, the next generation of DREADD agonists are needed and a thorough understanding of structure-activity relationships (SARs) of DREADDs is required for developing such ligands. We therefore conducted the first SAR studies of hM3Dq. We explored multiple regions of the scaffold represented by CNO, identified interesting SAR trends, and discovered several compounds that are very potent hM3Dq agonists but do not activate the native human M3 receptor (hM3). We also discovered that the approved drug perlapine is a novel hM3Dq agonist with >10000-fold selectivity for hM3Dq over hM3.

Homobivalent ligands of the atypical antipsychotic clozapine: Design, synthesis, and pharmacological evaluation

To date all typical and atypical antipsychotics target the dopamine D 2 receptor. Clozapine represents the best-characterized atypical antipsychotic, although it displays only moderate (submicromolar) affinity for the dopamine D2 receptor. Herein, we present the design, synthesis, and pharmacological evaluation of three series of homobivalent ligands of clozapine, differing in the length and nature of the spacer and the point of attachment to the pharmacophore. Attachment of the spacer at the N4′ position of clozapine yielded a series of homobivalent ligands that displayed spacer-length-dependent gains in affinity and activity for the dopamine D 2 receptor. The 16 and 18 atom spacer bivalent ligands were the highlight compounds, displaying marked low nanomolar receptor binding affinity (1.41 and 1.35 nM, respectively) and functional activity (23 and 44 nM), which correspond to significant gains in affinity (75- and 79-fold) and activity (9- and 5-fold) relative to the original pharmacophore, clozapine. As such these ligands represent useful tools with which to investigate dopamine receptor dimerization and the atypical nature of clozapine.

DIBENZO[b,e][1,4]DIAZEPINE MODULATORS OF DOPAMINE RECEPTORS, SEROTONIN RECEPTORS, ADRENERGIC RECEPTORS, ACETYLCHOLINE RECEPTORS, AND/OR HISTAMINE RECEPTORS

The present invention relates to new dibenzo[b,e][1,4]diazepine modulators of dopamine receptors, serotonin receptors, adrenergic receptors, acetylcholine receptors, and/or histamine receptors, pharmaceutical compositions thereof, and methods of use thereof.

Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics

Histamine H3 receptor (H3R) antagonists have some antipsychotic properties although the clear molecular mechanism is still unknown. As actually the most effective and less side effective antipsychotics are drugs with multiple targets

AMINO SUBSTITUTED DIARYL[A,D]CYCLOHEPTENE ANALOGS AS MUSCARINIC AGONISTS AND METHODS OF TREATMENT OF NEUROPSYCHIATRIC DISORDERS

Disclosed herein are analogs of clozapine and pharmaceutically acceptable salts, esters, amides, or prodrugs thereof; methods of synthesizing the analogs; and methods of using the analogs for treating neuorpsychiatric disorders. In some embodiments, the analogs are amino substituted diaryl[a,d]cycloheptenes.

Method of synthesis and isolation of solid N-desmethylclozapine and crystalline forms thereof

Disclosed herein are crystalline Forms A, B, C, D, and E of N-desmethylclozapine, methods of preparing the same, pharmaceutical compositions comprising the same, and methods of therapeutic treatment involving N-desmethylclozapine polymorphic forms.

Synthesis and preliminary pharmacological evaluation of 4′-arylmethyl analogues of clozapine. I - The effect of aromatic substituents

As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4′-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.