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Clozapine N-oxide

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Clozapine N-oxide
Names
IUPAC name 3-chloro-6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-11H-benzobenzodiazepine
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.164.243 Edit this at Wikidata
PubChem CID
UNII
CompTox Dashboard (EPA)
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,8-11H2,1H3Key: OGUCZBIQSYYWEF-UHFFFAOYSA-N
SMILES
  • C1(CCN(CC1)C2=NC3=C(C=CC(=C3)Cl)NC4=CC=CC=C42)
Properties
Chemical formula C18H19ClN4O
Molar mass 342.83 g·mol
Hazards
GHS labelling:
Pictograms GHS06: ToxicGHS07: Exclamation mark
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 , 100 kPa). Infobox references
Chemical compound
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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), despite the initial belief that it was biologically inert. However, it has been shown to not enter the brain after administration 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. These off-target effects mean behavioral data using the CNO-DREADD system have to be interpreted with caution.

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

References

  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.
  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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