氯氮平杂质
- CAS号:1977-07-7
- 英文名:11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine
- 中文名:氯氮平杂质
- CBNumber:CB21316359
- 分子式:C18H20N4
- 分子量:292.38
- MOL File:1977-07-7.mol
- 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 :solid
- 颜色 :Yellow
氯氮平杂质性质、用途与生产工艺
- 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。
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靶点
Ki: 6.3 nM (hM 3 Dq), 4.2 nM (hM 4 Di)
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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.
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