1977-07-7
基本信息
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
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
109-01-3
![5,11-二氢苯并[B][1,4]苯并二氮杂卓-6-酮](/CAS/GIF/5814-41-5.gif)
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
Ki: 6.3 nM (hM 3 Dq), 4.2 nM (hM 4 Di)
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.
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. |