Guanoxabenz (Hydroxyguanabenz)
(Synonyms: 胍诺沙苄,Hydroxyguanabenz) 目录号 : GC32662
Guanabenz (GBZ, GA, Wytensin, Wy-8678,BR-750) is an orally active central alpha 2-adrenoceptor (α2 adrenergic receptor) agonist with antihypertensive action.
Cas No.:24047-25-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.00%
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Guanabenz (GBZ, GA, Wytensin, Wy-8678,BR-750) is an orally active central alpha 2-adrenoceptor (α2 adrenergic receptor) agonist with antihypertensive action.
Interleukin-6 (IL6), colony stimulating factor 2 (Csf2), and cyclooxygenase-2 (Cox2) are downregulated by guanabenz-driven phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Although expression of IL1β and Tumor Necrosis Factor-α (TNFα) was suppressed by guanabenz, their downregulation was not directly mediated by eIF2α signaling.[2]
[1] B Holmes, et al. Drugs. 1983 Sep;26(3):212-29. [2] Takigawa S, et al. Int J Mol Sci. 2016 May 5;17(5):674.
| Cas No. | 24047-25-4 | SDF | |
| 别名 | 胍诺沙苄,Hydroxyguanabenz | ||
| Canonical SMILES | ClC1=C(/C=N/NC(NO)=N)C(Cl)=CC=C1 | ||
| 分子式 | C8H8Cl2N4O | 分子量 | 247.08 |
| 溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.0473 mL | 20.2364 mL | 40.4727 mL |
| 5 mM | 0.8095 mL | 4.0473 mL | 8.0945 mL |
| 10 mM | 0.4047 mL | 2.0236 mL | 4.0473 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Delineation of three pharmacological subtypes of alpha 2-adrenoceptor in the rat kidney
Br J Pharmacol 1991 Nov;104(3):657-64.PMID:1665747DOI:10.1111/j.1476-5381.1991.tb12485.x.
1. Simultaneous computer modelling of plain and ARC 239- and guanoxabenz-masked [3H]-RX821002 saturation curves, plain ARC 239 and Guanoxabenz competition curves as well as ARC 239-masked Guanoxabenz competition curves revealed that the drugs bound to three alpha 2-adrenoceptor subtypes in the rat kidney with grossly differing selectivities. These alpha 2-adrenoceptor subtypes were termed alpha 2 A, alpha 2B1 and alpha 2B2. The order of affinities for [3H]-RX821002 for the adrenoceptor sites was alpha 2A greater than alpha 2B1 greater than alpha 2B2, the KdS being 0.62 +/- 0.05, 2.52 +/- 0.11 and 6.74 +/- 1.21 nM, respectively. The order of affinities for ARC 239 was alpha 2B1 greater than alpha 2B2 much greater than alpha 2A with KdS 4.78 +/- 1.04, 28.8 +/- 4.1 and 1460 +/- 270 nM, respectively. For Guanoxabenz the order of affinities was alpha 2A greater than alpha 2B1 much greater than alpha 2B2 with KdS 99.7 +/- 15.1, 508 +/- 135 and 25,400 +/- 2400 nM, respectively. 2. Binding constants for 14 compounds for the three rat kidney alpha 2-adrenoceptor subtypes were determined by the simultaneous computer modelling of plain and ARC 239- and guanoxabenz-masked drug competition curves, plain ARC 239 and Guanoxabenz competition curves as well as ARC 239-masked Guanoxabenz competition curves. Of the 14 compounds tested, oxymetazoline and guanfacine were found to bind with low affinities to both of the alpha 2B1- and alpha 2B2-adrenoceptor but with high affinity to the alpha 2A-adrenoceptor. 3. (-)-Adrenaline and (-)-noradrenaline showed dissimilar order of affinities for the three alpha2-adrenoceptors. For (-)-adrenaline the order of affinities was alpha2Bl >- alpha2A> alpha2B2 and for (-)-noradrenaline alpha2B2 > alpha2Bl > alpha2A. All three alpha2-adrenoceptors showed the expected stereoselective binding for adrenaline enantiomers, the (+)-form being 7-10 fold less potent than the (-)form. 4. [3H]-yohimbine was also used as radioligand. The data with this ligand were fully compatible with the [3H]-RX821002 data. However, [3H]-yohimbine appeared to label only alpha2Bl- and alpha2B2-adrenoceptors presumably because it had too low an affinity for alpha2A-adrenoceptors. 5. We conclude that three pharmacological subtypes of alpha2-adrenoceptors are labelled by [3H]-RX821002 in the rat kidney. Guanoxabenz and ARC 239 may be used in competition studies to delineate between these three alpha2-adrenoceptor subtypes. Moreoever, we here present a method allowing the determination of binding constants for an arbitrary drug to the three alpha2-adrenoceptor subtypes.
Microsomal catalyzed N-hydroxylation of guanabenz and reduction of the N-hydroxylated metabolite: characterization of the two reactions and genotoxic potential of Guanoxabenz
Chem Res Toxicol 1996 Jun;9(4):682-8.PMID:8831810DOI:10.1021/tx9502047.
The N-reduction of the centrally acting alpha 2-adrenoreceptor agonist Guanoxabenz (Benzérial), an N-hydroxyamidinohydrazone, to the amidinohydrazone guanabenz (Wytensin, Hipten, Rexitene) by microsomal fractions from rabbits, pigs and humans has been detected in vitro. The conversion rates with rabbit microsomal fractions were markedly slower than those in the cases of fractions from humans and pigs. It was also possible to demonstrate the N-oxidation of guanabenz to Guanoxabenz by the use of microsomal fractions from rabbits, pigs, and humans. Furthermore, the oxidation was also observed in reconstituted systems in the presence of enriched cytochrome P450 fractions, purified isoenzyme P450 2C3, and heterologously expressed P450 2C3 of the subforms 6 beta H and 6 beta L. The analyses were performed with a newly developed HPLC technique and were confirmed by LC-MS methods. The kinetic parameters determined for the metabolic cycle (bioreversible reactions) are indicative of a predominance of the reduction of Guanoxabenz to guanabenz in vivo. Accordingly, Guanoxabenz in part constitutes a prodrug of guanabenz. Examination of guanabenz and Guanoxabenz for mutagenicity by means of the Ames test revealed that Guanoxabenz has pronounced mutagenic effects in the strains TA 98 and TA 1537. Guanabenz did not exhibit mutagenicity so that the N-reduction of Guanoxabenz has significance in terms of detoxification.
alpha 2-Adrenoceptor agonists induced mydriasis in the rat by an action within the central nervous system
Br J Pharmacol 1983 Mar;78(3):507-15.PMID:6132641DOI:10.1111/j.1476-5381.1983.tb08810.x.
1 The effects of intravenous administration of the selective alpha 2-adrenoceptor agonists clonidine, UK 14,304 and Guanoxabenz on rat pupil diameter were investigated. 2 In rats anaesthetized with pentobarbitone, each agonist produced a marked dose-related increase in pupil diameter; the rank order of potency was: clonidine greater than UK 14,304 greater than Guanoxabenz. 3 Pretreatment with the selective alpha 2-adrenoceptor antagonist, RX 781094 (0.5 mg/kg, i.v.), produced a parallel 30-40 fold shift to the right of the dose-pupil dilator response curves for the three agonists. Yohimbine (1.5 mg/kg, i.v.) produced about a 10 fold rightward shift of the dose-response curve for Guanoxabenz. In contrast, the alpha 1-selective antagonist, prazosin (0.5 mg/kg, i.v.), failed to affect the dose-response relation for Guanoxabenz. 4 Several antagonists of varying selectivities towards alpha 1- and alpha 2-adrenoceptors were tested for their ability to reverse the maximal mydriasis induced by Guanoxabenz (0.3 mg/kg, i.v.). The rank order of potency of the antagonists producing a 50% reversal of this effect was: RX 781094 greater than yohimbine greater than piperoxan = rauwolscine greater than mianserin greater than RS 21361. Neither corynanthine nor prazosin reversed the guanoxabenz-induced mydriasis. 5 Topical application of RX 781094 (0.1 to 3% w/v solutions) onto one eye produced a slow reversal of guanoxabenz-induced mydriasis; the time course and degree of reversal were virtually the same in both eyes. 6 Intracerebroventricular administration of RX 781094 (1.25-15 micrograms total dose) caused a rapid dose-related reversal of the maximal mydriasis induced by Guanoxabenz (0.3 mg/kg, i.v.). 7 Guanoxabenz (0.3 and 1.0 mg/kg, i.v.) did not produce any dilation of the physostigmine-constricted undamaged pupil of the pithed rat. Intravenous adrenaline was found to produce a small mydriatic effect, while atropine completely antagonized the effects of physostigmine in this preparation. 8 These results indicate that alpha 2-adrenoceptor agonists induce mydriasis in the rat through a central alpha 2-adrenoceptor mechanism. However, the site of action within the central nervous system remains to be determined.
Formation of Guanoxabenz from guanabenz in human liver. A new metabolic marker for CYP1A2
Drug Metab Dispos 1997 Nov;25(11):1266-71.PMID:9351903doi
The in vitro N-hydroxylation of guanabenz as well as the corresponding N-dehydroxylation of Guanoxabenz has been previously detected in biotransformation studies with microsomal fractions of different species including human hepatic microsomes. Furthermore, the N-hydroxylation of guanabenz was found to be catalyzed by enriched cytochrome P450 (P450) fractions in reconstituted systems. Strong correlations between 7-ethoxyresorufin O-deethylation (r = 0. 96; p < 0.001), caffeine N-demethylation (r = 0.92; p < 0.001), respectively, and guanabenz N-hydroxylation activities were demonstrated in 10 human liver microsomal preparations. Studies with microsomes from human B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes proved that CYP1A2 is the major isozyme responsible for this metabolic pathway. Further, P450 isozymes did not show any detectable conversion rates. The reaction was inhibited in presence of the potent CYP1A2 inhibitors alpha-naphthoflavone (7, 8-benzoflavone) and furafylline. The N-reduction of Guanoxabenz to guanabenz exhibits a significant correlation to the benzamidoxime N-reduction after incubation with 10 human liver microsomal preparations (r = 0.97; p < 0.001). The formation of benzamidine from benzamidoxime was described previously to be catalyzed by the benzamidoxime reductase. These results suggest that the guanabenz N-hydroxylation is mediated via CYP1A2, whereas the corresponding Guanoxabenz N-reduction is catalyzed by an enzyme system composed of cytochrome b5, NADH cytochrome b5-reductase, and benzamidoxime reductase. The high affinity of guanabenz to CYP1A2 and the distinct selectivity of this P450 isozyme toward guanabenz confirms the in vitro guanabenz N-hydroxylation to be a suitable metabolic marker for CYP1A2 in biotransformation studies.
Characterization of the enzymatic activity for biphasic competition by Guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) at alpha2-adrenoceptors. II. Description of a xanthine-dependent enzymatic activity in spleen cytosol
Biochem Pharmacol 1998 Nov 1;56(9):1121-8.PMID:9802321DOI:10.1016/s0006-2952(98)00136-1.
The mechanism for formation of high affinity binding of Guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) to alpha2-adrenoceptors by the rat spleen cytosol was studied. We report here that the spleen cytosolic fraction mediated the reduction of Guanoxabenz to guanabenz (1-(2,6-dichlorobenzylidene-amino)-3-guanidine), the latter having an almost 100-fold higher affinity for rat alpha2A-adrenoceptors than Guanoxabenz itself. The reaction product could be separated by high-performance liquid chromatography and its identity as guanabenz confirmed by nuclear magnetic resonance. The spleen cytosolic activity could be separated into high and low molecular weight components, the high molecular weight component requiring low molecular weight factors for maximal activity. Xanthine oxidase seems to be the most likely candidate responsible for the activity, as the guanoxabenz-reducing activity of the high molecular weight component could be sustained by exogenously applied xanthine, while it was potently blocked by allopurinol. The conversion of Guanoxabenz by the cytosolic activity was also quite potently blocked by DWO1, 1-(3,4-dimethoxybenzylideneamino)3-hydroxyguanidine, a hydroxyguanidine analogue to Guanoxabenz.