ChemSpider 2D Image | 8-Chloro-11-(4-methyl-4-oxido-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepine | C18H19ClN4O

8-Chloro-11-(4-methyl-4-oxido-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepine

  • Molecular FormulaC18H19ClN4O
  • Average mass342.823 Da
  • Monoisotopic mass342.124725 Da
  • ChemSpider ID2717

More details:

Validated by Experts, Validated by Users, Non-Validated, Removed by Users

10H-Dibenzo[b,e][1,4]diazepine, 8-chloro-11-(4-methyl-4-oxido-1-piperazinyl)- [ACD/Index Name]
8-Chlor-11-(4-methyl-4-oxido-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepin [German] [ACD/IUPAC Name]
8-Chloro-11-(4-methyl-4-oxido-1-piperazinyl)-10H-dibenzo[b,e][1,4]diazepine [ACD/IUPAC Name]
8-Chloro-11-(4-méthyl-4-oxydo-1-pipérazinyl)-10H-dibenzo[b,e][1,4]diazépine [French] [ACD/IUPAC Name]
34233-69-7 [RN]
3-chloro-6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-5H-benzo[b][1,4]benzodiazepine
Clozapine N-oxide
Clozapine N-oxide (CNO) (freebase)
  • Experimental Physico-chemical Properties
  • Miscellaneous

    • Bio Activity:

      <p><span style="text-decoration: underline;"><strong>Overview</strong></span></p> <p>Clozapine N-oxide CNO) is the prototypical chemical actuator for various DREADDs. It is a metabolite of the atypical antipsychotic <a title="Clozapine | Hello Bio" href="/clozapine.html" target="_blank" rel="noopener">clozapine</a>.</p> <p><br /><span style="text-decoration: underline;"><strong>Uses</strong></span><br /><span style="text-decoration: underline;">‘Excitatory’ (G<sub>q</sub>- coupled) DREADDs</span>:</p> <p>CNO activates the excitatory G<sub>q</sub>- coupled DREADDs: hM3Dq, hM1Dq and hM5Dq (pEC<sub>50</sub> values are 7.26 and 8.61 at hM3Dq and hM1Dq respectively).</p> <p>The hM3Dq DREADD is typically used for enhancing neuronal firing and activity (G<sub>q</sub>- signaling in neuronal and non-neuronal cells).</p> <p><span style="text-decoration: underline;">‘Inhibitory’ (G<sub>i</sub>- coupled) DREADDs</span>:</p> <p>CNO also activates the inhibitory hM4Di and hM2Di G<sub>i</sub>-coupled DREADDs (pEC<sub>50</sub> = 6.89 at hM4Di).</p> <p>The hM4Di DREADD is the most commonly used inhibitory DREADD and is used for neuronal silencing.</p> <p><span style="text-decoration: underline;">Gs and ?-arrestin coupled DREADDs:</span></p> <p>CNO also activates the G<sub>s</sub>- coupled DREADD (GsD) and the ?-arrestin preferring DREADD: rM3Darr (Rq(R165L).</p> <p><br />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.</p> <p>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)).</p> <p><br />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.</p> <p><br />CNO has proved to be an effective actuator of muscarinic DREADDs and provided controls are in place, will continue to be an excellent tool. <a title="Compound 21 (DREADD agonist 21) dihydrochloride | Hello Bio" href="/dreadd-agonist21-dihydrochloride.html" target="_self">Compound 21 (DREADD agonist 21)</a> represents an alternative to CNO for in vivo studies in which metabolic conversion of CNO to clozapine is an issue (Thompson et al 2019).</p> <p><br /><span style="text-decoration: underline;">Administration</span><br />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 <a title="CNO stability, solubility and use | Hello Bio" href="/clozapine-n-oxide-stability-solubility-review/#dose.html" target="_self">Technical review (table 3)</a> for example administration methods and doses.</p> <p><br /><strong><span style="text-decoration: underline;">Water soluble Clozapine N-oxide (CNO) dihydrochloride is also available:</span></strong></p> <p><a title="Clozapine N-oxide (CNO) dihydrochloride | Hello Bio" href="/clozapine-n-oxide-dihydrochloride.html" target="_blank" rel="noopener">Clozapine N-oxide (CNO) dihydrochloride</a> is water soluble and easier to solubilise and handle. Our stability studies have found that this product does not precipitate in aqueous solution unlike the freebase form of CNO (which due to its inherent chemical properties requires careful handling, has been shown in the literature to precipitate in solution under certain conditions and batch to batch variation in solubility can occur). </p> <p><br />In rhesus macaques, CNO dihydrochloride shows improved bioavailability compared to CNO freebase with less conversion to clozapine</p> <p><span style="text-decoration: underline;"><strong><br />Stability Studies</strong></span><br />For more info on the stability of CNO (freebase) and water-soluble CNO dihydrochloride, please see the following guides:</p> <ul> <li><a title="Clozapine N-Oxide (freebase) - a technical review on stability, solubility and use in the lab" href="/clozapine-n-oxide-stability-solubility-review">Clozapine N-Oxide (freebase) - a technical review on stability, solubility and use in the lab</a></li> <li><a title="Stability of Water-Soluble DREADD ligands in Solution: A Technical Review" href="/stability-of-water-soluble-dreadd-ligands-in-solution-a-technical-review/">Stability of Water-Soluble DREADD ligands in Solution: A Technical Review</a><br /><br /></li> </ul> Hello Bio HB1807
      <p><span style=text-decoration: underline;><strong>Overview</strong></span></p> <p>Clozapine N-oxide CNO) is the prototypical chemical actuator for various DREADDs. It is a metabolite of the atypical antipsychotic <a href=/clozapine.html title=Clozapine | Hello Bio target=_blank>clozapine</a>.</p> <p><br /><span style=text-decoration: underline;><strong>Uses</strong></span><br /><span style=text-decoration: underline;>&lsquo;Excitatory&rsquo; (G<sub>q</sub>- coupled) DREADDs</span>:</p> <p>CNO activates the excitatory G<sub>q</sub>- coupled DREADDs: hM3Dq, hM1Dq and hM5Dq (pEC<sub>50</sub> values are 7.26 and 8.61 at hM3Dq and hM1Dq respectively).</p> <p>The hM3Dq DREADD is typically used for enhancing neuronal firing and activity (G<sub>q</sub>- signaling in neuronal and non-neuronal cells).</p> <p><span style=text-decoration: underline;>&lsquo;Inhibitory&rsquo; (G<sub>i</sub>- coupled) DREADDs</span>:</p> <p>CNO also activates the inhibitory hM4Di and hM2Di G<sub>i</sub>-coupled DREADDs (pEC<sub>50</sub> = 6.89 at hM4Di).</p> <p>The hM4Di DREADD is the most commonly used inhibitory DREADD and is used for neuronal silencing.</p> <p><span style=text-decoration: underline;>Gs and &beta;-arrestin coupled DREADDs:</span></p> <p>CNO also activates the G<sub>s</sub>- coupled DREADD (GsD) and the &beta;-arrestin preferring DREADD: rM3Darr (Rq(R165L).</p> <p><br />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.</p> <p>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)).</p> <p><br />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.</p> <p><br />CNO has proved to be an effective actuator of muscarinic DREADDs and provided controls are in place, will continue to be an excellent tool. <a href=/dreadd-agonist21-dihydrochloride.html title=Compound 21 (DREADD agonist 21) dihydrochloride | Hello Bio target=_self>Compound 21 (DREADD agonist 21)</a> represents an alternative to CNO for in vivo studies in which metabolic conversion of CNO to clozapine is an issue (Thompson et al 2019).</p> <p></p> <p><br /><span style=text-decoration: underline;>Administration</span><br />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 <a href=/clozapine-n-oxide-stability-solubility-review/#dose.html title=CNO stability, solubility and use | Hello Bio target=_self>Technical review (table 3)</a> for example administration methods and doses.</p> <p><br /><strong><span style=text-decoration: underline;>Water soluble Clozapine N-oxide (CNO) dihydrochloride is also available:</span></strong></p> <p><a href=/clozapine-n-oxide-dihydrochloride.html title=Clozapine N-oxide (CNO) dihydrochloride | Hello Bio target=_blank>Clozapine N-oxide (CNO) dihydrochloride</a> is water soluble and easier to solubilise and handle. Our stability studies have found that this product does not precipitate in aqueous solution unlike the freebase form of CNO (which due to its inherent chemical properties requires careful handling, has been shown in the literature to precipitate in solution under certain conditions and batch to batch variation in solubility can occur).</p> <p><br />In rhesus macaques, CNO dihydrochloride shows improved bioavailability compared to CNO freebase with less conversion to clozapine</p> Hello Bio HB1807
      Biochemicals & small molecules/Agonists & activators Hello Bio HB1807
      Prototypical DREADD activator. Clozapine metabolite. Hello Bio HB1807
      Receptors & Transporters/G protein coupled receptors/DREADD Hello Bio HB1807

Predicted data is generated using the ACD/Labs Percepta Platform - PhysChem Module, version: 14.00

Density:
Boiling Point:
Vapour Pressure:
Enthalpy of Vaporization:
Flash Point:
Index of Refraction:
Molar Refractivity:
#H bond acceptors: 5
#H bond donors: 1
#Freely Rotating Bonds: 1
#Rule of 5 Violations: 0
ACD/LogP: 1.13
ACD/LogD (pH 5.5): -0.74
ACD/BCF (pH 5.5): 1.00
ACD/KOC (pH 5.5): 1.00
ACD/LogD (pH 7.4): -0.53
ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 7.4): 1.52
Polar Surface Area: 45 Å2
Polarizability:
Surface Tension:
Molar Volume:

Predicted data is generated using the US Environmental Protection Agency�s EPISuite™ 

                        
 Log Octanol-Water Partition Coef (SRC):
    Log Kow (KOWWIN v1.67 estimate) =  0.16

 Boiling Pt, Melting Pt, Vapor Pressure Estimations (MPBPWIN v1.42):
    Boiling Pt (deg C):  638.80  (Adapted Stein & Brown method)
    Melting Pt (deg C):  277.44  (Mean or Weighted MP)
    VP(mm Hg,25 deg C):  1.42E-017  (Modified Grain method)
    Subcooled liquid VP: 8.66E-015 mm Hg (25 deg C, Mod-Grain method)

 Water Solubility Estimate from Log Kow (WSKOW v1.41):
    Water Solubility at 25 deg C (mg/L):  4927
       log Kow used: 0.16 (estimated)
       no-melting pt equation used

 Water Sol Estimate from Fragments:
    Wat Sol (v1.01 est) =  373.78 mg/L

 ECOSAR Class Program (ECOSAR v0.99h):
    Class(es) found:
       Aliphatic Amines
       Vinyl/Allyl Halides

 Henrys Law Constant (25 deg C) [HENRYWIN v3.10]:
   Bond Method :   1.73E-020  atm-m3/mole
   Group Method:   Incomplete
 Henrys LC [VP/WSol estimate using EPI values]:  1.304E-021 atm-m3/mole

 Log Octanol-Air Partition Coefficient (25 deg C) [KOAWIN v1.10]:
  Log Kow used:  0.16  (KowWin est)
  Log Kaw used:  -18.150  (HenryWin est)
      Log Koa (KOAWIN v1.10 estimate):  18.310
      Log Koa (experimental database):  None

 Probability of Rapid Biodegradation (BIOWIN v4.10):
   Biowin1 (Linear Model)         :   0.4210
   Biowin2 (Non-Linear Model)     :   0.0078
 Expert Survey Biodegradation Results:
   Biowin3 (Ultimate Survey Model):   2.0358  (months      )
   Biowin4 (Primary Survey Model) :   3.0063  (weeks       )
 MITI Biodegradation Probability:
   Biowin5 (MITI Linear Model)    :  -0.2479
   Biowin6 (MITI Non-Linear Model):   0.0004
 Anaerobic Biodegradation Probability:
   Biowin7 (Anaerobic Linear Model): -1.5881
 Ready Biodegradability Prediction:   NO

Hydrocarbon Biodegradation (BioHCwin v1.01):
    Structure incompatible with current estimation method!

 Sorption to aerosols (25 Dec C)[AEROWIN v1.00]:
  Vapor pressure (liquid/subcooled):  1.15E-012 Pa (8.66E-015 mm Hg)
  Log Koa (Koawin est  ): 18.310
   Kp (particle/gas partition coef. (m3/ug)):
       Mackay model           :  2.6E+006 
       Octanol/air (Koa) model:  5.01E+005 
   Fraction sorbed to airborne particulates (phi):
       Junge-Pankow model     :  1 
       Mackay model           :  1 
       Octanol/air (Koa) model:  1 

 Atmospheric Oxidation (25 deg C) [AopWin v1.92]:
   Hydroxyl Radicals Reaction:
      OVERALL OH Rate Constant = 357.9397 E-12 cm3/molecule-sec
      Half-Life =     0.030 Days (12-hr day; 1.5E6 OH/cm3)
      Half-Life =    21.515 Min
   Ozone Reaction:
      OVERALL Ozone Rate Constant =     1.275830 E-17 cm3/molecule-sec
      Half-Life =     0.898 Days (at 7E11 mol/cm3)
      Half-Life =     21.558 Hrs
   Fraction sorbed to airborne particulates (phi): 1 (Junge,Mackay)
    Note: the sorbed fraction may be resistant to atmospheric oxidation

 Soil Adsorption Coefficient (PCKOCWIN v1.66):
      Koc    :  3.439E+005
      Log Koc:  5.536 

 Aqueous Base/Acid-Catalyzed Hydrolysis (25 deg C) [HYDROWIN v1.67]:
    Rate constants can NOT be estimated for this structure!

 Bioaccumulation Estimates from Log Kow (BCFWIN v2.17):
   Log BCF from regression-based method = 0.500 (BCF = 3.162)
       log Kow used: 0.16 (estimated)

 Volatilization from Water:
    Henry LC:  1.73E-020 atm-m3/mole  (estimated by Bond SAR Method)
    Half-Life from Model River: 6.275E+016  hours   (2.615E+015 days)
    Half-Life from Model Lake : 6.846E+017  hours   (2.852E+016 days)

 Removal In Wastewater Treatment:
    Total removal:               1.85  percent
    Total biodegradation:        0.09  percent
    Total sludge adsorption:     1.76  percent
    Total to Air:                0.00  percent
      (using 10000 hr Bio P,A,S)

 Level III Fugacity Model:
           Mass Amount    Half-Life    Emissions
            (percent)        (hr)       (kg/hr)
   Air       4.01e-005       0.694        1000       
   Water     48.5            1.44e+003    1000       
   Soil      51.4            2.88e+003    1000       
   Sediment  0.0955          1.3e+004     0          
     Persistence Time: 1.19e+003 hr

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