Clozapine N-oxide (CNO) (Synonyms: CNO) |
| Catalog No.GC10822 |
Clozapine N-oxide (CNO)는 강력한 도파민 항체이며 또한 강력하고 선택적인 무스카린 M4 수용체 (EC50 = 11 nM) 활성제이다.
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Cas No.: 34233-69-7
Sample solution is provided at 25 µL, 10mM.
Clozapine N-oxide (CNO)는 강력한 도파민 항체이며 또한 강력하고 선택적인 무스카린 M4 수용체 (EC50 = 11 nM) 활성제이다.CNO는 클로자핀의 주요 메타볼라이트이자 인간 무스카린 디자이너 수용체 (DREADDs)의 활성제이다[1][2]. Clozapine N-oxide (CNO)는 DREADD 수용체 hM3Dq와 hM4Di를 활성화한다. Clozapine N-oxide (CNO)는 약리학적으로 무활성인 분자로서 수용체에 대한 친과력이 현저하지 않다 (<1 μm)[3]. Clozapine N-oxide (CNO)는 로봇과 인간에서 높은 생물이용도를 가지고 있다[4].
Clozapine N-oxide (CNO)는 작은 쥐의 피질세포에서 5-HT2 수용체의 밀도를 현저히 감소시킨다. 연구에서 작은쥐의 피질세포에서 5-HT2 수용체 밀도와 5-HT2A 수용체 mRNA 수준이 현저히 감소했다는 사실이 발견되었다[7].
β-R-q와 β-R-s Tg 쥐 모두에서 Clozapine N-oxide (CNO) 치료는 혈당 수준을 용량-의존적으로 낮추고 Plasma 인슐린 농도를 증가시켜 β 세포 G 단백질 신호링의 정도가 투여된 Clozapine N-oxide (CNO) 복용량에 따라 조절될 수 있다는 것을 보여준다[8]. rM3Dq를 표현하는 쥐의 뇌하수체 β-세포에 Clozapine N-oxide (CNO)를 식용물을 통해 구강 투여하여 현저한 대사형태를 일으켜 상당량의 Clozapine N-oxide (CNO)가 위장 기관에서 흡수된다는 것을 나타낸다[9]. 약물 Clozapine N-oxide (CNO)에 의해 선택적으로 활성화되는 진화된 G 단백질 커플드 수용체(hM3Dq)를 표현하는 전기기형 마우스를 만들었다. 지방전위 뇌파와 단일뉴런 기록은 주변 투여 Clozapine N-oxide (CNO)가 hM3Dq를 표현하는 쥐의 해마뇌세포를 선택적으로 활성화하는 것을 밝혀냈다. 뉴런 활성화의 행동 상관은 운동 증가, 스테로타이피 그리고 정서성 뇌진탭을 포함한다[10].
References:
[1]: Wess J, Nakajima K, et,al. Novel designer receptors to probe GPCR signaling and physiology. Trends Pharmacol Sci. 2013 Jul;34(7):385-92. doi: 10.1016/j.tips.2013.04.006. Epub 2013 Jun 13. PMID: 23769625; PMCID: PMC3758874.
[2]: Manvich DF, Webster KA, et,al. The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice. Sci Rep. 2018 Mar 1;8(1):3840. doi: 10.1038/s41598-018-22116-z. PMID: 29497149; PMCID: PMC5832819.
[3]: Weiner DM, Meltzer HY, et,al. The role of M1 muscarinic receptor agonism of N-desmethylclozapine in the unique clinical effects of clozapine. Psychopharmacology (Berl). 2004 Dec;177(1-2):207-16. doi: 10.1007/s00213-004-1940-5. Epub 2004 Jul 16. PMID: 15258717.
[4]: Bender D, Holschbach M, et,al. Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice. Nucl Med Biol. 1994 Oct;21(7):921-5. doi: 10.1016/0969-8051(94)90080-9. PMID: 9234345.
[5]: Silva RR, Parreiras-E-Silva LT, et,al. Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D2 Receptor. Front Pharmacol. 2019 Jun 4;10:628. doi: 10.3389/fphar.2019.00628. PMID: 31214037; PMCID: PMC6558205.
[6]: Zorn SH, Jones SB, et,al. Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol. 1994 Nov 15;269(3):R1-2. doi: 10.1016/0922-4106(94)90047-7. PMID: 7895765.
[7]: Heiser P, Schulte E, et,al. Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):297-302. doi: 10.1016/j.pnpbp.2003.10.008. PMID: 14751426.
[8]: Guettier JM, Gautam D, et,al. A chemical-genetic approach to study G protein regulation of beta cell function in vivo. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19197-202. doi: 10.1073/pnas.0906593106. Epub 2009 Oct 26. PMID: 19858481; PMCID: PMC2767362.
[9]: Jain S, Ruiz de Azua I, et,al. Chronic activation of a designer G(q)-coupled receptor improves β cell function. J Clin Invest. 2013 Apr;123(4):1750-62. doi: 10.1172/JCI66432. Epub 2013 Mar 8. PMID: 23478411; PMCID: PMC3613926.
[10]:Alexander GM, Rogan SC, et,al. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron. 2009 Jul 16;63(1):27-39. doi: 10.1016/j.neuron.2009.06.014. PMID: 19607790; PMCID: PMC2751885.
| 세포 실험 [1]: | |
세포 라인 | 새끼쥐의 피질세포 |
제조 방법 | 체외 조건에서 24시간 후에 Clozapine N-oxide (CNO) (200/400 ng/ml) 처리를 받은 대쥐 원생 피질세포의 수용체 수치（밀도、친화력 및 mRNA 수준）및 글리세랄dehyde 3-fosfate dehydrogenase (GAPDH) mRNA 수준이다. |
반응 조건 | Clozapine N-oxide(CNO) (200/400 ng/ml)， 24시간 동안 |
응용 분야 | 원생 피질세포에서 5-HT2 수용체 밀도（Clozapine N-oxide (CNO) 200/400/200과 Cloz-N-oxide 200 대대군）및 5-HT2A 수용체 mRNA 수준（Clozapine N-oxide (CNO) 200 대대군）이 현저히 감소했습니다. |
| 동물 실험 [2]: | |
동물 모형 | β-RQ 및 β-RS Tg 쥐 |
제조 방법 | β세포 G q/11 혹은 G S 신호 경로의 급성 활성화가 포도당 홈스태시스에 미치는 체내 효과를 판단하기 위해 쥐에게 다양한 복용량의 Clozapine N-oxide (CNO) (0.0001-10 mg/kg)를 주입하고 2시간 동안 혈당 수준을 배양했습니다. 실험이 시작되기 전에 모든 쥐는 자유롭게 먹을 수 있었습니다. |
제형 | 0.0001-10 mg/kg Clozapine N-oxide(CNO) ,2 시간 동안 |
응용 분야 | β-R-q와 β-R-s 트랜스제닉 쥐에서 Clozapine N-oxide (CNO) 치료는 혈당 수준의 용량-의존적인 하강과 혈장 인슐린 농도의 증가를 불렀고 β 세포 G 단백질 신호의 정도가 복용된 Clozapine N-oxide (CNO) 복용량에 따라 조절될 수 있다는 것을 보여줍니다. |
참고문헌: [1]: Heiser P, Schulte E, et,al. Effects of clozapine and its metabolites on the 5-HT2 receptor system in cortical and hippocampal cells in vitro. Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):297-302. doi: 10.1016/j.pnpbp.2003.10.008. PMID: 14751426.[2]: Guettier JM, Gautam D, et,al. A chemical-genetic approach to study G protein regulation of beta cell function in vivo. Proc Natl Acad Sci U S A. 2009 Nov 10;106(45):19197-202. doi: 10.1073/pnas.0906593106. Epub 2009 Oct 26. PMID: 19858481; PMCID: PMC2767362. | |
| Cas No. | 34233-69-7 | SDF | |
| Synonyms | CNO | ||
| Chemical Name | 3-chloro-6-(4-methyl-4-oxidopiperazin-4-ium-1-yl)-5H-benzo[b][1,4]benzodiazepine | ||
| Canonical SMILES | C[N+]1(CCN(CC1)C2=C3C=CC=CC3=NC4=C(N2)C=C(C=C4)Cl)[O-] | ||
| Formula | C18H19ClN4O | M.Wt | 342.82 |
| Solubility |
≥ 17.15 mg/mL in DMSO, ≥ 49 mg/mL in Water with gentle warming This product is unstable in solution and it is recommended to prepare and use it immediately. |
Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.917 mL | 14.5849 mL | 29.1698 mL |
| 5 mM | 0.5834 mL | 2.917 mL | 5.834 mL |
| 10 mM | 0.2917 mL | 1.4585 mL | 2.917 mL |
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One week after the injection of AAV-DIO-hM4D(Gi)-mCherry/AAV-DIO-hM3D-mCherry or AAV-DIO-mCherry and before the behavioral tests, clozapine N-oxide, CNO (3.3 mg kg-1, i.p.)(GLPBIO) was scheduled 15 minutes prior to the test.
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Related Biological Data
Chemogenetic activation of MCH neurons induced anxiety-like behaviors in mice.(C) Effects of 0.3 mg/kg and 0.15 mg/kg CNO on OFT, EPM and MBT in wild type mice. (n = 6–8 mice per group).
On the experiment day, CNO (0.15 mg/kg)(GLPBIO) was injected intraperitoneally to induce the activation of hM3Dqpositive MCH neurons in the LHA 20 min prior to the anxiety behaviors tests.
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