Clozapine N-oxide

Clozapine N-oxide
Names
	IUPAC name 3-chloro-6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-11H-benzo[b][1,4]benzodiazepine
Identifiers
CAS Number	34233-69-7;
3D model (JSmol)	Interactive image;
ChEMBL	ChEMBL1688;
ChemSpider	21169512;
ECHA InfoCard	100.164.243
PubChem CID	135445691;
UNII	MZA8BK588J;
CompTox Dashboard (EPA)	DTXSID50955778 ;
	InChI InChI=1S/C18H19ClN4O/c1-23(24)10-8-22(9-11-23)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3 Key: OGUCZBIQSYYWEF-UHFFFAOYSA-N;
	SMILES C[N+]1(CCN(CC1)C2=NC3=C(C=CC(=C3)Cl)NC4=CC=CC=C42)[O-];
Properties
Chemical formula	C18H19ClN4O
Molar mass	342.83 g·mol−1
Hazards
	GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H301, H315, H319, H335
Precautionary statements	P261, P264, P270, P271, P280, P301+P310, P302+P352, P304+P340, P305+P351+P338, P312, P321, P330, P332+P313, P337+P313, P362, P403+P233, P405, P501
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Clozapine N-oxide (CNO) is a synthetic drug used mainly in biomedical research as a ligand to activate Designer Receptors Exclusively Activated by Designer Drugs (DREADDs),^[1] despite the initial belief that it was biologically inert. However, it has been shown to not enter the brain after administration^[2] and to reverse metabolize in peripheral tissues to form clozapine. Clozapine can bind to a number of different serotonergic, dopaminergic and adrenergic receptors within the brain.^[3] These off-target effects mean behavioral data using the CNO-DREADD system have to be interpreted with caution.^[4]

Alternatives to CNO with more affinity, more inert character, and faster kinetics include Compound 21 (C21)^[5] and deschloroclozapine (DCZ).^[6]

References

^ Armbruster, B. N.; Li, X.; Pausch, M. H.; Herlitze, S.; Roth, B. L. (2007-03-02). "Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand". Proceedings of the National Academy of Sciences. 104 (12): 5163–5168. Bibcode:2007PNAS..104.5163A. doi:10.1073/pnas.0700293104. ISSN 0027-8424. PMC 1829280. PMID 17360345.
^ Gomez, Juan L.; Bonaventura, Jordi; Lesniak, Wojciech; Mathews, William B.; Sysa-Shah, Polina; Rodriguez, Lionel A.; Ellis, Randall J.; Richie, Christopher T.; Harvey, Brandon K.; Dannals, Robert F.; Pomper, Martin G. (2017-08-04). "Chemogenetics revealed: DREADD occupancy and activation via converted clozapine". Science. 357 (6350): 503–507. Bibcode:2017Sci...357..503G. doi:10.1126/science.aan2475. ISSN 1095-9203. PMC 7309169. PMID 28774929.
^ Manvich, Daniel F.; Webster, Kevin A.; Foster, Stephanie L.; Farrell, Martilias S.; Ritchie, James C.; Porter, Joseph H.; Weinshenker, David (2018-03-01). "The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice". Scientific Reports. 8 (1): 3840. Bibcode:2018NatSR...8.3840M. doi:10.1038/s41598-018-22116-z. ISSN 2045-2322. PMC 5832819. PMID 29497149.
^ This article incorporates text available under the CC BY 4.0 license. Ju, William (November 1, 2023). Neuroscience. Toronto: University of Toronto. 3.4 Chemogenic methods to examine the brain behaviour.
^ Bonaventura, Jordi; Eldridge, Mark A. G.; Hu, Feng; Gomez, Juan L.; Sanchez-Soto, Marta; Abramyan, Ara M.; Lam, Sherry; Boehm, Matthew A.; Ruiz, Christina; Farrell, Mitchell R.; Moreno, Andrea (2019-10-11). "High-potency ligands for DREADD imaging and activation in rodents and monkeys". Nature Communications. 10 (1): 4627. Bibcode:2019NatCo..10.4627B. doi:10.1038/s41467-019-12236-z. ISSN 2041-1723. PMC 6788984. PMID 31604917.
^ Nagai, Yuji; Miyakawa, Naohisa; Takuwa, Hiroyuki; Hori, Yukiko; Oyama, Kei; Ji, Bin; Takahashi, Manami; Huang, Xi-Ping; Slocum, Samuel T.; DiBerto, Jeffrey F.; Xiong, Yan (September 2020). "Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys". Nature Neuroscience. 23 (9): 1157–1167. doi:10.1038/s41593-020-0661-3. ISSN 1546-1726. PMID 32632286. S2CID 220375204.

[1] Armbruster, B. N.; Li, X.; Pausch, M. H.; Herlitze, S.; Roth, B. L. (2007-03-02). "Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand". Proceedings of the National Academy of Sciences. 104 (12): 5163–5168. Bibcode:2007PNAS..104.5163A. doi:10.1073/pnas.0700293104. ISSN 0027-8424. PMC 1829280. PMID 17360345.

[2] Gomez, Juan L.; Bonaventura, Jordi; Lesniak, Wojciech; Mathews, William B.; Sysa-Shah, Polina; Rodriguez, Lionel A.; Ellis, Randall J.; Richie, Christopher T.; Harvey, Brandon K.; Dannals, Robert F.; Pomper, Martin G. (2017-08-04). "Chemogenetics revealed: DREADD occupancy and activation via converted clozapine". Science. 357 (6350): 503–507. Bibcode:2017Sci...357..503G. doi:10.1126/science.aan2475. ISSN 1095-9203. PMC 7309169. PMID 28774929.

[3] Manvich, Daniel F.; Webster, Kevin A.; Foster, Stephanie L.; Farrell, Martilias S.; Ritchie, James C.; Porter, Joseph H.; Weinshenker, David (2018-03-01). "The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice". Scientific Reports. 8 (1): 3840. Bibcode:2018NatSR...8.3840M. doi:10.1038/s41598-018-22116-z. ISSN 2045-2322. PMC 5832819. PMID 29497149.

[Neuroscience_University_of_Toronto-4] This article incorporates text available under the CC BY 4.0 license. Ju, William (November 1, 2023). Neuroscience. Toronto: University of Toronto. 3.4 Chemogenic methods to examine the brain behaviour.

[5] Bonaventura, Jordi; Eldridge, Mark A. G.; Hu, Feng; Gomez, Juan L.; Sanchez-Soto, Marta; Abramyan, Ara M.; Lam, Sherry; Boehm, Matthew A.; Ruiz, Christina; Farrell, Mitchell R.; Moreno, Andrea (2019-10-11). "High-potency ligands for DREADD imaging and activation in rodents and monkeys". Nature Communications. 10 (1): 4627. Bibcode:2019NatCo..10.4627B. doi:10.1038/s41467-019-12236-z. ISSN 2041-1723. PMC 6788984. PMID 31604917.

[6] Nagai, Yuji; Miyakawa, Naohisa; Takuwa, Hiroyuki; Hori, Yukiko; Oyama, Kei; Ji, Bin; Takahashi, Manami; Huang, Xi-Ping; Slocum, Samuel T.; DiBerto, Jeffrey F.; Xiong, Yan (September 2020). "Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys". Nature Neuroscience. 23 (9): 1157–1167. doi:10.1038/s41593-020-0661-3. ISSN 1546-1726. PMID 32632286. S2CID 220375204.

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