1977-07-7

中文名称氯氮平杂质

英文名称 11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine

CAS 1977-07-7

分子式 C18H20N4

分子量 292.38

MOL 文件 1977-07-7.mol

1977-07-7 结构式

基本信息物理化学性质制备方法常见问题列表

基本信息

中文别名

去氯氯氮平
11-(4-甲基-1-哌嗪基)-5H-二苯并[B,E][1,4]二氮杂卓
11-(4-甲基哌嗪-1-基)-5H-二苯并[B,E] [1,4]二氮杂卓

英文别名

Dechloroclozapine
Dopamine serotonin antagonist-1
11-(4-Methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine
11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine
5H-Dibenzo[b,e][1,4]diazepine, 11-(4-methyl-1-piperazinyl)-

物理化学性质

沸点457.5±55.0 °C(Predicted)

密度1.22±0.1 g/cm3(Predicted)

储存条件Keep in dark place,Inert atmosphere,Room temperature

溶解度DMSO : ≥ 83.3 mg/mL (284.90 mM)

酸度系数(pKa)7.82±0.20(Predicted)

形态固体

颜色黄色

制备方法

方法1

109-01-3

5814-41-5

1977-07-7

以N-甲基哌嗪和5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮为原料合成11-(4-甲基哌嗪-1-基)-5H-二苯并[b,E][1,4]二氮杂卓的一般步骤：将5,10-二氢-11H-二苯并[b,e][1,4]二氮杂卓-11-酮（105 mg，0.5 mmol）置于50 mL圆底烧瓶中。依次加入N,N-二甲基苯胺（36.3 mg，0.3 mmol）。在130°C条件下，加入适量超干三氯氧磷和磁力搅拌子，在氮气保护下，将混合物在回流条件下搅拌12小时。反应完成后，蒸馏除去过量的三氯氧磷。随后，加入适量N-甲基哌嗪继续搅拌12小时，反应终止。通过薄层色谱（TLC）监测反应进程。反应混合物用乙酸乙酯（3×70 mL）萃取，依次用水洗涤。合并有机层，加入无水Na2SO4干燥。过滤后，浓缩残余物。通过柱色谱（洗脱剂：二氯甲烷/甲醇 = 25:1）纯化，得到110 mg目标产物11-(4-甲基哌嗪-1-基)-5H-二苯并[b,E][1,4]二氮杂卓，产率为75%。

参考文献：

[1] Patent: CN108586364, 2018, A. Location in patent: Paragraph 0150; 0151; 0152

常见问题列表

生物活性

Deschloroclozapine 是有效的，高亲和力的，选择性的，代谢稳定的基于毒蕈碱的 DREADDs 的激动剂。Deschloroclozapine 抑制 [3H] 苄基喹啉基 (QNB) 与 hM3Dq 和 hM4Di 的结合，Ki 值分别为 6.3 和 4.2 nM。据报道 Deschloroclozapine 在小鼠和非人类灵长类动物中都有多种用途。

靶点

Ki: 6.3 nM (hM ₃ Dq), 4.2 nM (hM ₄ Di)

体外研究

Deschloroclozapine has greater potencies for DREADDs than previous agonists in vitro. Deschloroclozapine is a potent agonist for hM ₃ Dq with an EC ₅₀ =0.13 nM. Deschloroclozapine is also a potent agonist for hM ₄ Di with an EC ₅₀ =0.081 nM.
Deschloroclozapine is a potent and selective agonist for hM ₃ Dq and hM ₄ Di, it does not display significant agonistic activity for any of the 318 tests wild-type GPCRs at <10 nM.

体内研究

Deschloroclozapine (100 μg/kg; i.v.) exhibits good brain concentration profiles and biostability. Pharmacokinetic studies confirmed that Deschloroclozapine is rapidly accumulated in mouse brains and monkey CSF, while its metabolites are negligible.
Deschloroclozapine (1 μg/kg; i.p.) selectively and rapidly enhances neuronal activity via hM ₃ Dq-DREADD in vivo, Deschloroclozapine can also be utilized for in vivo neuronal silencing by activating hM ₄ Di, an inhibitory DREADD.
Deschloroclozapine (1-100 μg/kg; i.v.) selectively induces hM ₃ Dq-mediated metabolic activity.
Deschloroclozapine (100 μg/kg; i.m.) selectively induces behavioral deficits in hM ₄ Di-expressing monkeys.

Animal Model:	Macaque monkey; 2.8-8.0 kg; age 3-10 years
Dosage:	10, 100, 1000, 10000 μg/kg
Administration:	I.v. bolus injection
Result:	Required the dose for 50% occupancy (ED ₅₀ ) for Deschloroclozapine was 25 μg/kg.

Animal Model:	Macaque monkey; 2.8-8.0 kg; age 3-10 years
Dosage:	100 μg/kg (Pharmacokinetic Analysis)
Administration:	I.v. injection
Result:	Provided a sufficient concentration of Deschloroclozapine by a low systemic dose of Deschloroclozapine to be available for hM ₄ Di-DREADD binding in vivo for at least for 2 h without the production of metabolites in monkeys.

Animal Model:	Wild-type C57BL/6j mice; male; age >12 weeks
Dosage:	100 μg/kg (Pharmacokinetic Analysis)
Administration:	I.p. administration
Result:	Diminished rapidly of Deschloroclozapine concentration and were undetectable at 2 h in either brain tissue or CSF. The amount of the desmethyl metabolite C21 in CSF was negligible.

Animal Model:	HM ₃ Dq monkeys and non-DREADD monkeys
Dosage:	1, 3, 100 μg/kg (Pharmacokinetic Analysis)
Administration:	I.v. injection
Result:	Increased of FDG uptaking after Deschloroclozapine administration occurred exclusively at the hM ₃ Dq-positive area.

Animal Model:	Monkeys received multiple injections of an AAV-vector carrying hM ₄ Di genes
Dosage:	100 μg/kg (Pharmacokinetic Analysis)
Administration:	I.m. administration
Result:	Enabled a rapidly and reversibly-induced behavioral change through activating muscarinic-based DREADDs without significant side effects.