Clozapine N-oxide (CNO) dihydrochloride (water soluble)

(HB6149)
Technical documents: SDS CoA Datasheet

Product overview

Name Clozapine N-oxide (CNO) dihydrochloride (water soluble)
Description Dihydrochloride salt of CNO - the prototypical DREADD activator
Alternative names CNO dihydrochloride, CNO.2HCl
Purity >98%
Customer comments

We have been using Clozapine N-oxide (CNO) dihydrochloride (CNO.2HCl) from Hello Bio. We are fully satisfied with this product: it is readily water soluble and stable. We have administered CNO-2HCl to animals via IP injection and intracranial microinjection; and we have observed CNO-induced cellular and behavioral effects fully consistent with its expected activation of DREADD receptors." Verified customer, UTHSC

Great product. Great company and product. Better pricing & similar quality compared to the most of the other companies. We used CNO dihydrochloride for both i.p. and drinking water delivery, and it worked fine. Nice service. Verified customer, University of Minnesota

Works as expected, and significantly cheaper than alternatives. Will use this for future CNO purchases Verified customer, UCSF

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Biological Data

Biological description

Overview

Clozapine N-oxide dihydrochloride (CNO) is the dihydrochloride salt of CNO which is the prototypical chemical DREADDs activator. It is a metabolite of clozapine. In rhesus macaques, CNO dihydrochloride shows improved bioavailability compared to CNO freebase with less conversion to clozapine 


Uses
‘Excitatory’ (Gq- coupled) DREADDs:

CNO activates the excitatory Gq- coupled DREADDs: hM3Dq, hM1Dq and hM5Dq (pEC50 values are 7.26 and 8.61 at hM3Dq and hM1Dq respectively).

The hM3Dq DREADD is typically used for enhancing neuronal firing and activity (Gq- signaling in neuronal and non-neuronal cells).

‘Inhibitory’ (Gi- coupled) DREADDs:

CNO also activates the inhibitory hM4Di and hM2Di Gi-coupled DREADDs (pEC50 = 6.89 at hM4Di).

The hM4Di DREADD is the most commonly used inhibitory DREADD and is used for neuronal silencing.

Gs and β-arrestin coupled DREADDs:

CNO also activates the Gs- coupled DREADD (GsD) and the β-arrestin preferring DREADD: rM3Darr (Rq(R165L).


Recent findings (Gomez et al 2017) suggest that systemically administered CNO does not readily cross the blood-brain-barrier in vivo, and converts to clozapine which activates DREADDs. Enzymatic and non-enzymatic reduction of CNO to clozapine has been shown in humans, rats, monkeys, guinea pigs and mice.

Care must therefore be taken in experimental design and proper controls should be incorporated, for example, the use of non-DREADD expressing animals may be appropriate (see Mahler and Aston-Jones (2018)).


Jendryka et al (2019) found that in mice, CNO does enter the brain and that unbound CNO is present in the brain at sufficient levels to activate DREADDs directly. Results suggested that CNO is a suitable DREADD agonist but requires between-subject controls for unspecific effects.


CNO has proved to be an effective actuator of muscarinic DREADDs and provided controls are in place, will continue to be an excellent tool. Compound 21 (DREADD agonist 21) represents an alternative to CNO for in vivo studies in which metabolic conversion of CNO to clozapine is an issue (Thompson et al 2019).


Administration
In the literature, CNO has been administered intraperitoneally (i.p.), subcutaneously, directly infused intracranially, via drinking water, osmotic mini-pump and recently via eye drops. See our Technical review (table 3) for example administration methods and doses.


Handling & stabliity

Our stability studies have shown that CNO dihydrochloride is easier to solubilize and handle and have found that this product does not precipitate in solution unlike the freebase form of CNO (which, due to its inherent chemical properties requires careful handling and has been shown in the literature to precipitate in aqueous solution under certain conditions). Please see our handling guidelines below.

Application notes


Other Non-CNO DREADD activators available:

Solubility & Handling

Storage instructions -20°C
Solubility overview Soluble in water (100 mM). Always store solutions at -20°C.
Handling

Storage of solid

  • Store at -20°C.
  • Please note that the compound is a hydroscopic solid and contact with air may cause material to become sticky. Product performance should not be affected but we recommend storing the material in a sealed jar.

Storage of solutions

  • Make up solutions and use immediately.
  • If storage of solutions is required, you should aliquot out the solution into tightly sealed vials and store at -20°C and store these for up to one month.
  • Allow the product to equilibrate to RT for at least one hour before opening and using.

Storage of solutions at room temperature

  • We recommend only keeping solutions at room temperature (25°C) for a few days as our studies have shown that after 96 hours the purity of the compound in solution drops to ~95% and will continue to drop over time.
Important This product is for RESEARCH USE ONLY and is not intended for therapeutic or diagnostic use. Not for human or veterinary use

Calculators

Molarity

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Dilution

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Chemical Data

Chemical name 8-Chloro-11-(4-methyl-4-oxido-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine dihydrochloride
Molecular Weight 415.74
Chemical structure Clozapine N-oxide dihydrochloride Chemical Structure
Molecular Formula C18H19ClN4O.2HCl
CAS Number 2250025-93-3
SMILES ClC(C=C1)=CC2=C1NC(C=CC=C3)=C3C(N4CC[N+](C)([O-])CC4)=N2.Cl.Cl
Source Synthetic
InChi InChI=1S/C18H19ClN4O.2ClH/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;2*1H
InChiKey MBRGKRXDVKTUPT-UHFFFAOYSA-N
Appearance Orange solid

References for Clozapine N-oxide (CNO) dihydrochloride (water soluble)

References are publications that support the biological activity of the product
  • A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques.

    Allen et al (2019) J Pharmacol Exp Ther 368(2) : 199-207
  • Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice.

    Jendryka et al (2019) Sci Rep. 9(1) : 4522
  • DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands.

    Goutaudier et al (2019) eNeuro 6 : (5)
  • CNO Evil? Considerations for the Use of DREADDs in Behavioral Neuroscience.

    Mahler and Aston-Jones (2018) Neuropsychopharmacology doi: 10.1038 : /npp.2016.251
  • DREADD Agonist 21 Is an Effective Agonist for Muscarinic-Based DREADDs in Vitro and in Vivo

    Thompson et al (2018) ACS Pharmacol. Transl. Sci. 10.1021 : /acsptsci.8b00012
Publications
These publications cite the use of Clozapine N-oxide (CNO) dihydrochloride (water soluble) purchased from Hello Bio:
  • A forebrain neural substrate for behavioral thermoregulation

    Jung et al (2022) Neuron. 110(2) : 266-279
    PubMedID: 34687664
  • Oestrogen engages brain MC4R signalling to drive physical activity in female mice

    Krause et al (2021) Nature. 599 : 131-135
    PubMedID: 34646010
  • Astrocytes regulate ultra-slow arteriole oscillations via stretch-mediated TRPV4-COX-1 feedback

    Haidey et al (2021) Cell Rep . 109405 : 36(5)
    PubMedID: 34348138
  • Estrogen Drives Melanocortin Neurons To Increase Spontaneous Activity and Reduce Sedentary Behavior

    Krause et al (2021) bioRxiv : https://doi.org/10.1101/794792
  • Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula

    Nuno-Perez et al (2021) Neuron. 109(6) : 947-956
    PubMedID: 33535028

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