A3317-1ml | Clozapine N-oxide (CNO) [34233-69-7] Clinisciences

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. Tyler Bland, et al. "Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer." Cell Rep Med. 2024 Feb 20;5(2):101388. PMID: 38262412
2. Lei Jia, Jieting Yin, et al. "Dopaminergic Neurons in the Ventral Tegmental Area to the Parabrachial Nucleus Promote the Emergence of Rats from Propofol Anesthesia." Research Square. 03 Nov, 2023.
3. Jie-Ying Chen, Ke Wu, et al. "The PrLGlu→ avBNSTGABA circuit rapidly modulates depression-like behaviors in male mice." iScience. 2023 Sep 12;26(10):107878. PMID: 37810240
4. Li-Xin Jiang, Geng-Di Huang, et al. "Diminished activation of excitatory neurons in the prelimbic cortex leads to impaired working memory capacity in mice." BMC Biol. 2023 Aug 11;21(1):171. PMID: 37568146
5. Xiaohui Bai, Kun Zhang, et al. "Selective activation of AKAP150/TRPV1 in ventrolateral periaqueductal gray GABAergic neurons facilitates conditioned place aversion in male mice." Commun Biol. 2023 Jul 17;6(1):742. PMID: 37460788
6. Rui Chen, Xiang Xu, et al. "The lateral habenula nucleus regulates pruritic sensation and emotion." Mol Brain. 2023 Jun 27;16(1):54. PMID: 37370111
7. Siqi Peng, Wenzhen Gu, et al. "A new AAV tool for highly preferentially targeting hippocampal CA2." Mol Brain. 2023 Jun 11;16(1):50. PMID: 37303064
8. Si-Yi Mo, Yang Xue, et al. "Descending serotonergic modulation from rostral ventromedial medulla to spinal trigeminal nucleus is involved in experimental occlusal interference-induced chronic orofacial hyperalgesia." J Headache Pain. 2023 May 10;24(1):50. PMID: 37165344
9. Jiantao Huo, Feng Du, et al. "Identification of brain-to-spinal circuits controlling the laterality and duration of mechanical allodynia in mice." Cell Rep. 2023 Apr 25;42(4):112300. PMID: 36952340
10. Ge Wang, Yun-Feng Liu, et al. "Short-term acute bright light exposure induces a prolonged anxiogenic effect in mice via a retinal ipRGC-CeA circuit." Sci Adv. 2023 Mar 22;9(12):eadf4651. PMID: 36947616
11. Yanbing Chen, Huimin Peng, et al. "A cingulate-hippocampal circuit mediates early depressive symptoms in Alzheimer's disease." bioRxiv. February 07, 2023.
12. 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
13. 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
14. 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
15. 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
16. 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
17. Laura A DeNardo, Cindy D Liu, et al."Temporal Evolution of Cortical Ensembles Promoting Remote Memory Retrieval." Nat Neurosci. 2019 Mar;22(3):460-469. PMID: 30692687

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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.