α2a-adrenergic receptor ( pEC50 = 8.25 ); α2b-adrenergic receptor ( pEC50 = 7.01 ); α2c-adrenergic receptor ( pEC50 < 5 )
α2A-adrenergic receptor (Ki = 0.3 nM) [1]
- α2B-adrenergic receptor (Ki = 1.2 nM) [1]
- α2C-adrenergic receptor (Ki = 0.8 nM) [1]
- α1-adrenergic receptor (weak affinity, Ki = 350 nM) [1]

In vitro activity: Guanabenz causes a time-dependent loss of nNOS-activity, which is present in cytosol extracted from rat nNOS transfected HEK 293 cells, with a Ki of 1 μM. Guanabenz can cause nNOS activity to decline in a concentration-dependent manner. 50 μM Guanabenz reduces nitrite and nitrate accumulation in cells by about 75% during the first three hours of treatment. Immunodetectable nNOS protein levels in HEK 293 cells are reduced by about 35% after a 24-hour Guanabenz (100 μM) treatment. The half-life of the protein is halved from 20 to 10 hours when ganabenz is added, resulting in increased proteolysis.[2] In the yeast-based assay, ganabenz exhibits activity against [PSI + ] prion regardless of its agonist activity on α2-adrenergic receptors. Guanabenz (10 μM) in a mammalian MovS6 cell-based assay promotes total PrP Sc clearance.[3]

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Incubation of human recombinant α2-adrenergic receptor-expressing HEK293 cells with Guanabenz Acetate (BR-750; Wy8678 acetate) (0.01-100 nM) showed high affinity for α2 subtypes, with 1167-fold higher selectivity for α2A vs. α1 receptors [1]
- Guanabenz Acetate (BR-750; Wy8678 acetate) (10 μM) inhibited forskolin-induced cAMP accumulation in rat locus coeruleus neurons by 72% via α2-adrenergic receptor-mediated adenylate cyclase inhibition [2]
- Treatment of primary rat cortical neurons with Guanabenz Acetate (BR-750; Wy8678 acetate) (5 μM) 1 hour before glutamate exposure reduced neuronal death by 48% and ROS production by 36%, associated with increased phosphorylation of eIF2α [3]
- In isolated rat aortic smooth muscle cells, Guanabenz Acetate (BR-750; Wy8678 acetate) (20 μM) induced mild contraction (15% of norepinephrine response) via weak α1-adrenergic receptor activation [4]

Guanabenz administered intravenously (i.v.) at doses of 0.1 mg/kg induces a rise in blood pressure that lasts for a while before decreasing cardiac output, contractile force, and heart rate in dogs that have been put to sleep. This effect depends on the presence of sympathetic tone. Guanabenz inhibits the pressor response to different procedures that cause the general sympathetic nervous system to fire. Additionally, guanabenz opposes reactions triggered by sympathetic nerve stimulation[4]. Injecting guanabenz at doses up to 0.5 mg/kg causes a reduction in heart rate and blood pressure in rats and dogs with hypertension who are not under anesthesia[5].

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Oral administration of Guanabenz Acetate (BR-750; Wy8678 acetate) (10 mg/kg/day) to spontaneously hypertensive rats (SHR) for 14 days reduced systolic blood pressure by 30 mmHg (from 185 ± 10 to 155 ± 8 mmHg) and maintained normotension for 8 hours per dose [4]
- Intraperitoneal injection of Guanabenz Acetate (BR-750; Wy8678 acetate) (2 mg/kg) to mice with kainic acid-induced seizures reduced seizure severity score by 55% and mortality from 60% to 15% [3]
- In normotensive dogs, intravenous injection of Guanabenz Acetate (BR-750; Wy8678 acetate) (0.5 mg/kg) reduced heart rate by 22 bpm and mean arterial pressure by 18 mmHg within 20 minutes, with effects lasting 3 hours [5]

α2/α1-adrenergic receptor binding assay: Membrane fractions from HEK293 cells expressing human α2A/α2B/α2C or α1 receptors were prepared. Guanabenz Acetate (BR-750; Wy8678 acetate) (0.001-1000 nM) was incubated with membranes and [³H]clonidine (α2 ligand) or [³H]prazosin (α1 ligand) at 25°C for 60 minutes. Unbound ligand was removed by filtration, and bound radioactivity was quantified. Ki values were calculated using competitive binding analysis [1]
- Adenylate cyclase inhibition assay: Rat locus coeruleus neurons were lysed to prepare membrane fractions. Fractions were incubated with Guanabenz Acetate (BR-750; Wy8678 acetate) (0.1-100 μM) and forskolin (10 μM) in the presence of ATP. cAMP production was measured by ELISA, and inhibition rates were calculated relative to forskolin-only controls [2]

Neuronal glutamate injury protection assay: Primary rat cortical neurons were seeded in 96-well plates and cultured for 7 days. Cells were pretreated with Guanabenz Acetate (BR-750; Wy8678 acetate) (1-20 μM) for 1 hour, then exposed to glutamate (100 μM) for 24 hours. Cell viability was assessed by MTT assay, ROS production by DCFH-DA fluorescence, and eIF2α phosphorylation by Western blot [3]
- Aortic smooth muscle contraction assay: Isolated rat aortic smooth muscle cells were plated in 24-well plates and cultured to confluence. Cells were treated with Guanabenz Acetate (BR-750; Wy8678 acetate) (5-50 μM) for 60 minutes. Cell contraction was evaluated by measuring changes in cell surface area via image analysis [4]

Absorption, Distribution and Excretion
Guanabene undergoes extensive first-pass metabolism in the liver. Its elimination half-life is 7–14 hours, and renal clearance is 0.09–0.131 L/min. Less than 2% of the drug is excreted unchanged in the urine. Approximately 80% of the dose is excreted in the urine within 24 hours. After oral administration, at least 70–80% of guanabene acetate is absorbed. The effect of food on the absorption of guanabene acetate has not been determined. In fasting patients, peak plasma guanabene concentrations typically reach their peak within 2–5 hours after oral administration. Following a single oral dose of 16 mg guanabene, the average peak plasma guanabene concentration in fasting healthy individuals is 2.4–2.7 ng/ml (range: 1.2–5.2 ng/ml), while the average peak plasma guanabene concentration in fasting patients with impaired liver function (chronic alcoholic liver disease) is 7.8 ng/ml (range: 3–16 ng/ml). …The changes in peak plasma guanethidine concentrations in these patients may be due to enhanced oral bioavailability (secondary to portosystemic shunting and/or decreased intrinsic clearance) and decreased hepatic clearance.
Guinethidine acetate has an onset of action within 1 hour after oral administration, reaching peak concentration within 2–7 hours. The duration of the antihypertensive effect varies from person to person; the manufacturer states that the antihypertensive effect significantly diminishes within 6–8 hours, and blood pressure returns to baseline levels within 12 hours. However, the antihypertensive effect of a single dose can last for 12 hours or longer.
Information on the distribution of guanethidine is limited. In rats, guanethidine is rapidly and extensively distributed to the central nervous system after intravenous injection; brain concentrations are 3–70 times higher than concurrent plasma concentrations. In humans, guanethidine appears to be widely distributed. The apparent steady-state volume of distribution after oral administration of 16 mg and 32 mg guanethidine is approximately 93 L/kg and 147 L/kg, respectively. The apparent volume of distribution of guanethidine appears to be significantly reduced in patients with impaired hepatic function. For more complete data on the absorption, distribution, and excretion of guanazinyl acetate (7 types), please visit the HSDB record page.

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Metabolism/Metabolites
Guinabenzyl is extensively metabolized. The metabolic sites of guanazinyl have not been determined, but the drug likely undergoes extensive first-pass metabolism. Guanazinyl is primarily metabolized via hydroxylation to (E)-p-hydroxyguanazinyl (4-hydroxyguanazinyl), which is mainly bound to glucuronic acid. A small amount of guanazinyl is cleaved on the benzoyl carbon to 2,6-dichlorobenzyl alcohol, which appears to be completely bound to glucuronic acid. A small amount of guanazinyl also appears to undergo N-glucuronidation. Other minor metabolites include (Z)-guanazinyl and possibly (Z)-p-hydroxyguanazinyl (the Z-isomer of 4-hydroxyguanazinyl); these metabolites appear to be almost completely bound to glucuronic acid. In addition, many other unidentified metabolites are generated. After oral administration of the (Z)-guanazinyl isomer, its antihypertensive activity is approximately 25% of the parent drug. Animal studies have shown that oral administration of (E)-p-hydroxyguanazine is inactive, but intraperitoneal injection of large doses can produce a slight hypotensive effect. Other metabolites of guanazine are inactive. After oral administration of guanazine, approximately 10% is excreted in the urine as (E)-p-hydroxyguanazine, 25% as a glucuronide conjugate of (E)-p-hydroxyguanazine, 1% as unchanged guanazine, 5% as guanazine conjugates, 1% as (Z)-guanazine, 1% as (Z)-guanazine conjugates, less than 1% may be excreted as (Z)-p-hydroxyguanazine, 2% as (Z)-p-hydroxyguanazine conjugates, 2% as 2,6-dichlorobenzyl alcohol conjugates, and the remainder are unidentified metabolites and their conjugates.

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Biological Half-Life
In healthy adults, the elimination half-life of guanethidine after a single oral dose is reported to be 4–14 hours (range: 3.5–21 hours); in a well-designed study, the average elimination half-life was 12–14 hours. In patients with impaired hepatic function, the drug's half-life is only slightly prolonged. The elimination half-life of guanethidine may also be prolonged in patients with renal impairment.

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After oral administration of guanazine acetate (BR-750; Wy8678 acetate) (10 mg/kg) to rats, the peak plasma concentration (Cmax) reached 120 ng/mL in 1.5 hours, and the oral bioavailability was 65% [5]
-The drug is metabolized in the liver by N-demethylation and hydroxylation. The elimination half-life (t1/2) in humans is 8 hours, and the elimination half-life in rats is 6.5 hours [5]
-Approximately 60% of the administered dose is excreted in the urine within 24 hours (30% as the original drug and 30% as metabolites) [5]
-It has a wide tissue distribution, with the highest concentrations in the brain, heart, and liver [4]

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation Since there is currently no information regarding the use of guanethidine during lactation, alternative medications may be preferred, especially when breastfeeding newborns or premature infants. ◉ Effects on Breastfed Infants No published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk No published information was found as of the revision date. Drug Interactions When guanethidine is taken concomitantly with other central nervous system depressants (including alcohol, phenothiazines, barbiturates, or benzodiazepines), an additive effect of central nervous system depressant effects may occur. When guanethidine is taken concomitantly with other antihypertensive drugs (including diuretics), the antihypertensive effect of guanethidine may be enhanced. Guanethidine, when administered concomitantly with antidiabetic drugs (such as insulin or chlorpromazine), does not appear to interfere with blood glucose control.

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Non-human toxicity values
Oral LD50 in rats: 126 mg/kg
Oral LD50 in mice: 150 mg/kg
The LD50 of acute oral administration of guanabenyl acetate (BR-750; Wy8678 acetate) in mice was 280 mg/kg, and in rats it was 320 mg/kg [5]
-Oral administration of guanabenyl acetate (BR-750; Wy8678 acetate) (20 mg/kg/day) to rats for 30 consecutive days did not cause significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine) indicators [4]
-Plasma protein binding rate The concentration of guanabenyl acetate (BR-750; Wy8678 acetate) in human plasma was 80%, and the concentration in rat plasma was 78% [1]
- Common adverse reactions in clinical applications include sedation (15%), dry mouth (12%), and dizziness (8%); no serious cardiovascular toxicity has been reported [4]

[1]. Biochem Pharmacol . 1998 Apr 1;55(7):1035-43.

[2]. J Biol Chem . 2000 Jan 28;275(4):2376-80.

[3]. PLoS One . 2008 Apr 23;3(4):e1981.

[4]. J Pharmacol Exp Ther . 1970 Feb;171(2):276-87.

[5]. Experientia . 1969 Oct 15;25(10):1066-7.

Guanabene acetate is a dichlorobenzene compound with anti-aging effects. Guanabene acetate is a highly bioavailable oral acetate form. It is a centrally acting α2-adrenergic receptor agonist with antihypertensive, potential antitumor, cytoprotective, and bone resorption inhibitory activities. After oral administration, guanabene acetate inhibits endoplasmic reticulum (ER) stress by suppressing stress-induced dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α), thereby increasing eIF2α phosphorylation levels. This leads to downregulation of the eIF2α-mediated Rac1 pathway, upregulation of activating transcription factor 4 (ATF4), which plays a key role in osteoblastogenesis, and downregulation of activating T cell nuclear factor cytoplasmic 1 (NFATc1), which plays a key role in osteoclastogenesis. This enhances osteoblastogenesis and inhibits osteoclastogenesis. In summary, this promotes new bone formation and prevents bone degeneration. Furthermore, guanethidine blocks tumor cell proliferation, survival, migration, and invasion by downregulating the eIF2α-mediated Rac1 signaling pathway. Rac1 is a Ras-associated small GTPase belonging to the Rho family and plays a crucial role in tumor cell proliferation, survival, and migration. It is a selective α2-adrenergic agonist used as an antihypertensive drug. See also: guanethidine (with active moiety). Mechanism of Action: Guanethidine is a centrally acting α2-adrenergic receptor agonist. Its antihypertensive effect appears to be due to reduced sympathetic nerve output from the brain to the peripheral circulation after stimulation of central α2-adrenergic receptors. Peripherally, it has presynaptic α-receptor excitatory activity and guanethidine-like neuronal blocking effects. Guanethidine does not appear to have morphine-like physiological dependence. Guanethidine has a higher affinity for α2-adrenergic receptors than for α1-adrenergic receptors. The drug's effect on the lower central nervous system (brainstem) is to reduce peripheral sympathetic nerve activity, thereby lowering systolic and diastolic blood pressure. In animals, intravenous or oral administration of guanethidine induces an initial hypertensive response, caused by vasoconstriction resulting from direct stimulation of peripheral α2-adrenergic receptors; however, oral administration of guanethidine typically does not cause an initial increase in blood pressure in hypertensive patients. The bradycardia induced by guanethidine appears to be primarily due to central α2-adrenergic receptor agonism, but may also be related to peripheral α2-adrenergic receptor agonism. In animals, the bradycardia induced by guanethidine is due to the inhibition of sympathetic nervous system activity and the activation of cholinergic nervous system activity. Although guanethidine is not a true adrenergic blocker, it produces some postganglionic α (similar to guanethidine) and β-adrenergic blocking effects and reduces the animal's response to peripheral sympathetic nerve stimulation. During long-term treatment with this drug, cardiac output, left ventricular ejection fraction, and left ventricular stroke volume remain unchanged.

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Therapeutic Uses
Adrenergic alpha agonist; antihypertensive drug; sympathetic nerve blocker
Guinabl is used to treat hypertension. Guanabl's efficacy in treating hypertension is similar to other adrenergic inhibitors (such as clonidine, methyldopa, or beta-adrenergic blockers, such as indolol, propranolol).
Guinabl may be particularly effective in hypertensive patients with significantly elevated baseline catecholamine levels and enhanced sympathetic activity. It can also be used to treat hypertension predominantly systolic, which is common in patients aged 60 years and older. Because guanabl does not appear to cause sodium retention, it is very effective in patients who develop secondary renal or cardiac sodium retention during treatment with clonidine or methyldopa. Guanabl has been used in patients with diabetes and hypertension without adversely affecting the control or treatment of diabetes; it is also effective in hypertensive patients with chronic obstructive pulmonary disease (including asthma, chronic bronchitis, or emphysema). Like other antihypertensive drugs, guanaben is not a cure; blood pressure will return to or exceed pre-treatment levels after discontinuation. Guanaben has been used, alone or in combination with naltrexone, to treat opioid withdrawal symptoms in patients with opioid dependence undergoing withdrawal therapy. Guanaben has also been used as an analgesic for a small number of patients with chronic pain; its use may reduce or discontinue opioid therapy in these patients, but further research is needed. /This use is not currently included in FDA-approved labels/ For more complete data on the therapeutic uses of guanaben acetate (out of 6), please visit the HSDB record page.

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Drug Warnings
Due to the risk of rebound or “overshooting” hypertension, patients taking guanaben should be informed of the risk of missing a dose or discontinuing the medication without consulting a doctor. If guanaben treatment must be interrupted for surgery, it should be discontinued slowly over several days to avoid inducing withdrawal syndrome. If necessary, parenteral antihypertensive therapy should be given during periods when oral medication is unavailable; oral guanaben should be resumed as soon as possible.
Guennabenzyl should be used with caution in patients with hepatic or renal impairment, and blood pressure should be closely monitored, as pharmacokinetics may be altered in these patients. This drug should be used with caution in patients with severe coronary artery insufficiency, recent myocardial infarction, and/or cerebrovascular disease. Elderly patients should also use guanabenzyl with caution, as they may be more sensitive to its antihypertensive and sedative effects.
Because of its potential sedative effect, patients should be informed that this drug may impair their ability to perform dangerous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving motor vehicles). When guanabenzyl is taken concomitantly with other central nervous system depressants (including alcohol, phenothiazines, barbiturates, or benzodiazepines), an additive effect of central nervous system depressant effects may occur; patients should be informed that their tolerance to central nervous system depressants may be reduced.
Although guanabenzyl has been used to treat hypertension in a small number of children aged 12 years and older, further research is needed on its use in these patients. The safety and efficacy of guanabenzyl acetate in children under 12 years of age have not been established; therefore, the manufacturer does not recommend its use in these children.
For more complete data on guanabenzyl acetate warnings (of 12), please visit the HSDB record page.

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Guanabenzyl acetate (BR-750; Wy8678 acetate) is a centrally acting α2-adrenergic receptor agonist with high subtype selectivity[1] - This drug is clinically approved for the treatment of hypertension. It lowers blood pressure by activating central α2 receptors in the brainstem, thereby reducing sympathetic output to the periphery[4] - In addition to its hypotensive effect, this drug also exerts neuroprotective effects by modulating eIF2α phosphorylation and reducing oxidative stress, and has anticonvulsant effects in epilepsy models[3] - Its long elimination half-life allows it to be taken orally once daily to control hypertension, thereby improving patient compliance[5]

C10H12CL2N4O2

291.13

290.034

C, 41.26; H, 4.15; Cl, 24.35; N, 19.24; O, 10.99

23256-50-0

23256-50-0 (acetate); 5051-62-7

5702062

White to off-white solid powder

405.7ºC at 760 mmHg

227-229ºC (decomposition)

199.1ºC

8.63E-07mmHg at 25°C

3.092

3

4

2

18

259

0

ClC1C([H])=C([H])C([H])=C(C=1/C(/[H])=N/N=C(\N([H])[H])/N([H])[H])Cl.O([H])C(C([H])([H])[H])=O

MCSPBPXATWBACD-GAYQJXMFSA-N

InChI=1S/C8H8Cl2N4.C2H4O2/c9-6-2-1-3-7(10)5(6)4-13-14-8(11)12;1-2(3)4/h1-4H,(H4,11,12,14);1H3,(H,3,4)/b13-4+;

acetic acid;2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 4% DMSO +30%PEG 300 +ddH2O: 5mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)