Clozapine N-oxide (CNO)
Clozapine-N-oxide (CNO) is a metabolite of clozapine, which reduces the density of 5-HT2 receptor in rat primary cortical cells. [1] Clozapine-N-oxide (CNO) also activates an evolved M3-muscarinic receptor and then can be used in chemogenetics. [2]
Clozapine is a known atypical antipsychotic medication used in the treatment of schizophrenia. The two major metabolites of clozapine are norclozapine and clozapine-N-oxide (CNO) [3]. Clozapine is also formed from its N-oxide metabolite. It means that a reversible metabolic pathway exists for clozapine and clozapine-N-oxide (CNO) [4]. In rat primary cortical cells and SHS5Y5 neuroblastoma cells, a significant decrease was found for 5-HT2 receptor density with 200 ng/ml clozapine-N-oxide (CNO) [1]. About the method of identification, reversed-phase HPLC has been reported to detect clozapine and its two major metabolites in human plasma[5].
References:
1. P. Heiser, E. Schulte, C. Hausmann, R. Becker, H. Remschmidt, J. C. Krieg and H. Vedder, Prog Neuropsychopharmacol Biol Psychiatry 2004, 28, 297-302.
2. Armbruster BN1, Li X, Pausch MH, et al. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8.
3. S. A. Volpicelli, F. Centorrino, P. R. Puopolo, J. Kando, F. R. Frankenburg, R. J. Baldessarini and J. G. Flood, Clin Chem 1993, 39, 1656-1659.
4. M. W. Jann, Y. W. Lam and W. H. Chang, Arch Int Pharmacodyn Ther 1994, 328, 243-250.
5. A. Avenoso, G. Facciola, G. M. Campo, A. Fazio and E. Spina, J Chromatogr B Biomed Sci Appl 1998, 714, 299-308.
- 1. Qiaocheng Zhai, Yizhun Zeng, et al. "Time-restricted feeding entrains long-term behavioral changes through the IGF2-KCC2 pathway." iScience. 2022 Apr 18;25(5):104267. PMID: 35521538
- 2. Qingtao Sun, Jianping Zhang, et al. "Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer's disease." Nat Commun. 2022 Feb 22;13(1):998. PMID: 35194025
- 3. Sean D. Stocker, Megan M. Wenner, et al. "Activation of the Organum Vasculosum of the Lamina Terminalis Produces a Sympathetically Mediated Hypertension." Hypertension. 2022 Jan;79(1):139-149. PMID: 34809435
- 4. Santhosh D, Sherman J, et al. "Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention." Dis Model Mech. 2019 Oct 10. pii: dmm.041228. PMID: 31601549
- 5. Anderson AG, Gaffy CB, et al. "Inhibition of Epstein-Barr Virus Lytic Reactivation by the Atypical Antipsychotic Drug Clozapine." Viruses. 2019 May 17;11(5):450. PMID: 31108875
- 6. Laura A DeNardo, Cindy D Liu, et al."Temporal Evolution of Cortical Ensembles Promoting Remote Memory Retrieval." bioRxiv. 2018 April 5.
Storage | Store at -20°C |
M.Wt | 342.82 |
Cas No. | 34233-69-7 |
Formula | C18H19ClN4O |
Solubility | insoluble in EtOH; ≥17.15 mg/mL in DMSO; ≥49 mg/mL in H2O with gentle warming |
Chemical Name | 3-chloro-6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-5H-benzo[b][1,4]benzodiazepine |
SDF | Download SDF |
Canonical SMILES | C[N+]1(CCN(CC1)C2=C3C=CC=CC3=NC4=C(N2)C=C(C=C4)Cl)[O-] |
Shipping Condition | Small Molecules with Blue Ice, Modified Nucleotides with Dry Ice. |
General tips | We do not recommend long-term storage for the solution, please use it up soon. |
Cell experiment[1]: | |
Cell lines |
Rat cortical cells |
Preparation method |
The solubility of this compound in DMSO is > 10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
Reacting condition |
24 h, 200 ng/ml |
Applications |
Clozapine N-oxide (CNO) is one of major metabolites of clozapine. It significantly reduced the 5-HT2 receptor density in rat cortical cells[1]. In rat choroid plexus, clozapine-N-oxide inhibited phosphoinositide hydrolysis stimulated by 5-HT[2]. |
Clinical experiment [3]: | |
Clinical samples |
Male schizophrenic patients aged 34-50 years |
Dosage form |
At 8:00 a.m. 100 mg clozapine N-oxide in powdered form wrapped in a piece of wrapped wafer |
Application |
When administered clozapine, mean clozapine N-oxide plasma concentrations were slightly lower than the other clozapine metabolite desmethylclozapine at the 12 hour time point. When clozapine N-oxide was administered, plasma concentrations of clozapine at the 12 hour time point were twice the amount of clozapine N-oxide. After clozapine N-oxide administration, only one patient had detectable plasma desmethylclozapine levels. |
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
References: [1]. Heiser P, Schulte E, Hausmann C, et al. Effects of clozapine and its metabolites on the 5-HT 2 receptor system in cortical and hippocampal cells in vitro[J]. Progress In Neuro-psychopharmacology and Biological Psychiatry, 2004, 28(2): 297-302. [2]. Kuoppamki M, Syvlahti E, Hietala J. Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists[J]. European Journal of Pharmacology: Molecular Pharmacology, 1993, 245(2): 179-182. [3].Chang W H, Lin S K, Lane H Y, et al. Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients[J]. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 1998, 22(5): 723-739. |
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