Fenazaquin (EL436; XDE 436)   中文名称: 喹螨醚

Absorption, Distribution and Excretion
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. Overall recovery of the radiolabel was excellent (89.5-107.7% of the administered dose). Within 48 hours of treatment, approximately 75% of the radiolabel was recovered in the excreta, and by 72 hours after treatment, >84% was recovered. No sex-related differences in elimination were noted. Approximately 20% of the radiolabel was recovered in the urine with the remainder in the feces. Less than 1.6% of the radiolabel was recovered in the residual carcass or tissues and essentially no significant amount of radiolabel was recovered in the expired air. There are no available excretion studies following bile cannulation or intravenous (i.v.) administration to determine test material bioavailability (gastrointestinal absorption). Therefore, while the nearly 20% of the administered dose was absorbed before it was excreted in urine, it is not clear if any or all of the remaining dose (nearly 80%) that was found in feces was actually absorbed prior to its fecal elimination.

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Metabolism / Metabolites
Metabolism involved cleavage of the ether bond, with formation of the 4-hydroxyquinazoline and carboxylic acid derivatives. Other biotransformations included oxidation of one of the methyl groups on the alkyl side chain to produce either an alcohol, which was further metabolised by hydroxylation of the O-ether alkyl moiety, or a carboxylic acid, which was further metabolised by hydroxylation of the 2-position of the quinazoline ring.
EL-436 (Fenazaquin, 97.36-98.80% ai; EL-436 uniformly labeled on either the t-butyl-phenyl ring (phenyl; 97.33->99.9%, 4.23 and 5.44 uCi/mg) or the quinazoline-phenyl ring (quinazoline; 98.8-99.2%, 19.8 uCi/mg) was administered to groups of five male and five female Fischer 344 (F344/Crl) rats as a single 1 mg/kg or 30 mg/kg radiolabeled dose. A group of eight male and eight female rats received 14-daily doses of 1 mg/kg unlabeled test material followed by a single radiolabeled gavage dose. An additional group of three male and three female rats received a single 1 mg/kg radiolabel dose to determine elimination of the compound in expired air. ... In the urine, the primary metabolite was AN-1 (4-(2-hydroxy-1,1-dimethylethyl) phenylacetic acid) (24-29% of total urinary radioactivity) plus numerous minor metabolites. This metabolite was characterized by the absence of protons associated with the quinazoline portion of the molecule, indicating cleavage of the ether bridge. No significant differences between the sexes or dose groups were observed. Four primary metabolites and numerous minor metabolites were found in the feces. The parent compound, fenazaquin, represented 1.2-4.2% of the recovered radioactivity in the single or multiple low-dose groups and 11.5-20.6% of the recovered activity in single high-dose rats. Metabolite F1 (4.6-9.4% of the administered dose) had the phenyl and quinazoline rings and both sets of methylene protons intact, as well as the addition of a single oxygen atom to the phenyl-t-butyl portion of the parent molecule. Metabolite F-1A, a minor metabolite contributing 0.6-2.6% of the radioactivity, was characterized by intact phenyl and quinazoline rings and hydroxylation of the ethoxy bridge. Metabolite F-2 was the primary fecal metabolite identified (16.3-22.8% of the recovered radioactivity) and was similar to metabolite F1, but with the addition of two oxygen atoms and the loss of two hydrogen atoms to form a carboxylic acid on one of the methyl alky groups attached to the phenyl ring. Metabolite F3 contributed 6.5-12.6% of the recovered radioactivity and contained both the phenyl and quinazoline ring systems; however, the quinazoline ring had been hydroxylated and one of the methyl alkyl groups of the phenyl ring had been carboxylated. While the fecal metabolites were likely produced by the liver, it is not possible to exclude metabolism by intestinal microflora. These studies show that radiolabeled fenazaquin is rapidly metabolized and eliminated from male and female rats following treatment with either single or multiple low doses or following a single high dose of the compound. However, there is no information on biliary excretion or fecal/urinary elimination following iv administration.

Non-Human Toxicity Values
LC50 Rat inhalation 1.9 mg/L/ 4 hr
LD50 Rabbit dermal >5000 mg/kg
LD50 Mouse oral (female) 1480 mg/kg
LD50 Mouse oral (male) 2449 mg/kg
For more Non-Human Toxicity Values (Complete) data for Fenazaquin (7 total), please visit the HSDB record page.

Crop Protection Volume 12, Issue 4, June 1993, Pages 255-258

Fenazaquin is a member of quinazolines. It has a role as an acaricide and a mitochondrial NADH:ubiquinone reductase inhibitor.

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Mechanism of Action
Fenazaquin is a miticide that exhibits both contact and ovicidal activity against a broad spectrum of mite and certain insects by inhibiting mitochondrial electron transport at the Complex I site (NADH-ubiquinone reductase).
... In this study, ...the in vitro toxicity and mechanism of action of several putative complex I inhibitors that are commonly used as pesticides. The rank order of toxicity of pesticides to neuroblastoma cells was pyridaben > rotenone > fenpyroximate > fenazaquin > tebunfenpyrad. A similar order of potency was observed for reduction of ATP levels and competition for (3)H-dihydrorotenone (DHR) binding to complex I, with the exception of pyridaben (PYR). Neuroblastoma cells stably expressing the /rotenone/ (ROT)-insensitive NADH dehydrogenase of Saccharomyces cerevisiae (NDI1) were resistant to these pesticides, demonstrating the requirement of complex I inhibition for toxicity. ... PYR was a more potent inhibitor of mitochondrial respiration and caused more oxidative damage than ROT. The oxidative damage could be attenuated by NDI1 or by the antioxidants alpha-tocopherol and coenzyme Q(10). PYR was also highly toxic to midbrain organotypic slices. These data demonstrate that, in addition to ROT, several commercially used pesticides directly inhibit complex I, cause oxidative damage, and suggest that further study is warranted into environmental agents that inhibit complex I for their potential role in Parkinson's Disease.
Parkinson's disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I-inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ-1 over-expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ-1 knock-down impairs astrocyte-mediated neuroprotection against rotenone, and that each process involves astrocyte-released factors. To further investigate the mechanism behind these findings, we developed a high-throughput, plate-based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co-cultured neurons. We used this bioassay to show that DJ-1 deficiency-induced impairments in astrocyte-mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II-V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD-relevant finding because pesticide exposure is epidemiologically-linked with an increased risk for PD. Further investigations into our model suggested that astrocytic GSH and heme oxygenase-1 antioxidant systems are not central to the neuroprotective mechanism.

C20H22N2O

306.4015

306.173

120928-09-8

86356

Colorless crystals

1.1±0.1 g/cm3

461.0±33.0 °C at 760 mmHg

77.5-80 °C

165.1±15.6 °C

0.0±1.1 mmHg at 25°C

1.595

5.54

35.01

0

3

5

23

357

0

O(C1C2=C([H])C([H])=C([H])C([H])=C2N=C([H])N=1)C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]

DMYHGDXADUDKCQ-UHFFFAOYSA-N

InChI=1S/C20H22N2O/c1-20(2,3)16-10-8-15(9-11-16)12-13-23-19-17-6-4-5-7-18(17)21-14-22-19/h4-11,14H,12-13H2,1-3H3

Quinazoline, 4-(2-(4-(1,1-dimethylethyl)phenyl)ethoxy)-

EL 436; EL-436; EL436; XDE 436; XDE-436; XDE436.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。