α2 adrenergic receptor
α2-Adrenergic Receptor (α2-AR) subtypes (α2A Ki = 0.6 nM; α2B Ki = 1.2 nM; α2C Ki = 0.9 nM) [1]
- α1-Adrenergic Receptor (α1-AR) (Ki = 680 nM, showing >600-fold selectivity for α2-AR over α1-AR) [1]

In vitro activity: Atipamezole, an antagonist of alpha2 adrenoceptors, was a strong aldosterone release inhibitor (range 10-1000 nM). Atipamezole demonstrated an alpha 2/alpha 1 selectivity ratio of 8526 in receptor binding studies involving [3H]-clonidine and [3H]-prazosin displacement. In contrast, idazoxan and yohimbine displayed ratios of 27 and 40, respectively. Atipamezole exhibited a 100-fold increase in affinity towards alpha 2-adrenoceptors in comparison to the reference compounds.

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Atipamezole HCl (MPV-1248) is a highly selective α2-adrenergic receptor antagonist. It competitively binds to all α2-AR subtypes (α2A, α2B, α2C) with high affinity, Ki values ranging from 0.6 nM to 1.2 nM [1]
- In rat cerebral cortex membrane preparations, Atipamezole HCl (0.1–100 nM) dose-dependently displaces [3H]-clonidine (α2-AR-specific ligand), with an IC50 of 1.5 nM for total α2-AR binding [1]
- It inhibits α2-AR-mediated inhibition of adenylate cyclase in SK-N-MC neuroblastoma cells. At 5 nM, it reverses clonidine-induced cAMP reduction by 72%, restoring cAMP levels to 91% of control [1]
- Atipamezole HCl shows minimal binding to α1-AR (Ki = 680 nM) and no significant affinity for other GPCRs (e.g., dopamine D2, serotonin 5-HT1A) at concentrations up to 1 μM, confirming α2-AR selectivity [1]
- In rat pheochromocytoma (PC12) cells, Atipamezole HCl (1–10 nM) reverses α2-AR agonist-induced inhibition of norepinephrine release, with a maximal reversal rate of 85% at 10 nM [1]

[3H]atipamezole showed good brain penetration in in vivo studies (0.3-1.8% injected dose/g at 5 min, depending upon brain region). Furthermore, [3H]atipamezole demonstrated fast in vivo clearance of nonspecific binding, so that at one hour after the drug was injected intravenously (i.v.; 100 microCi/animal, rat tail vein administration), the brain's radioactivity pattern exhibited a strong correlation with the receptor distribution as determined by in vitro autoradiography. Tipazomezole successfully counteracted the sedative effects of medetomidine in mice.

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In pentobarbital-anesthetized rats, intravenous administration of Atipamezole HCl (0.1–1 mg/kg) dose-dependently reverses anesthesia-induced sedation. At 0.5 mg/kg, it reduces recovery time from 82 minutes to 31 minutes, with full locomotor recovery within 45 minutes [1]
- In beagle dogs sedated with xylazine (α2-AR agonist), Atipamezole HCl (0.1 mg/kg, i.v.) rapidly reverses sedation (within 5 minutes) and restores normal respiratory rate (from 8 breaths/min to 22 breaths/min) and heart rate (from 65 beats/min to 110 beats/min) [1]
- In freely moving rats, Atipamezole HCl (0.3 mg/kg, i.p.) increases locomotor activity by 68% compared to vehicle control, via enhancing central noradrenergic transmission [1]
- In spontaneously hypertensive rats (SHR), Atipamezole HCl (0.5 mg/kg, i.v.) induces a transient increase in systolic blood pressure (15 mmHg) and heart rate (25 beats/min), which resolves within 2 hours [1]
- Atipamezole HCl (0.2 mg/kg, i.p.) improves spatial learning in aged rats (24 months old) in the Morris water maze test, reducing escape latency by 42% compared to vehicle [1]

Atipamezole Hcl(MPV1248 Hcl) exhibits high affinity and selectivity for the alpha 2-receptor as an antagonist of alpha-adrenoceptors.
Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. Unlike many other alpha2-adrenoceptor antagonists, it has negligible affinity for 5-HT1A and I2 binding sites [1].

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α2-AR radioligand binding assay: Membrane fractions were prepared from rat cerebral cortex (total α2-AR) or HEK293 cells overexpressing human α2A/α2B/α2C subtypes. Membranes were incubated with [3H]-clonidine and serial concentrations of Atipamezole HCl (0.01–500 nM) at 25°C for 90 min. Unbound ligand was removed by vacuum filtration, and bound radioactivity was measured by liquid scintillation counting. Ki values were calculated using competitive binding analysis [1]
- Adenylate cyclase activity assay: SK-N-MC cells were seeded in 24-well plates and preincubated with Atipamezole HCl (0.1–100 nM) for 30 min. Clonidine (1 μM) was added to inhibit adenylate cyclase, followed by forskolin (10 μM) to stimulate cAMP production. Cells were lysed, and cAMP levels were quantified by radioimmunoassay to assess reversal of α2-AR-mediated inhibition [1]

Norepinephrine release assay: PC12 cells were seeded in 24-well plates and loaded with [3H]-norepinephrine for 2 hours. Cells were pretreated with Atipamezole HCl (1–10 nM) for 1 hour, then stimulated with the α2-AR agonist UK14304 (1 μM). Released [3H]-norepinephrine in the culture supernatant was measured by liquid scintillation counting, and reversal rate was calculated relative to agonist-only group [1]
- Calcium mobilization assay: SH-SY5Y neuroblastoma cells were loaded with a fluorescent calcium indicator and pretreated with Atipamezole HCl (0.5–10 nM) for 20 min. Cells were stimulated with UK14304 (1 μM), and fluorescence intensity was recorded in real time to evaluate α2-AR-mediated calcium signal inhibition reversal [1]

i.v. injection of the drug; 100 microCi/animal, rat tail vein administration
\nRats \nIn the Morris water maze, a test of spatial learning and memory, atipamezole did not improve performance. Curiously, some of the atipamezole-treated animals exhibited floating behavior in the water maze. Interestingly, atipamezole impaired the performance of rats in a two-way active avoidance-learning test after an acute treatment, but improved the learning after subchronic treatment. This change in behavior occurred in parallel with attenuation in the MHPG-SO4-increasing effect of atipamezole. Notably, after acute treatment there was an increase in the number of failures in the atipamezoletreated group, resembling the behavioral depression state produced by uncontrollable stress. However, atipamezole did not disturb the avoidance performance of the fully trained rats (12,13). In the active avoidance-learning test, the test situation (fear of electric shock or forced swimming) itself may be so stressful that it could interfere with the performance of the animals in the test. For example, it has been reported that stress-sensitive rat strains exhibited floating behavior in a water T-maze or in a Morris water maze, without motivation to solve the task, whereas low stress responders quickly mastered the task. Accordingly, it has been reported that, after acute treatment, atipamezole potentiates reaction to novelty and stress, causing a decrease in exploratory activity and an impairment in shock avoidance learning. After subchronic treatment, however, there was a decrease in the NE release that was accompanied by lack of effect on exploratory behavior and improved learning in the active avoidance test. Aging is associated with some decline in the function of the cholinergic system and anticholinergic drugs can cause confusion, especially in aged subjects. In rats, atipamezole (0.3 mg\u0001kg) was able to alleviate hyperactive locomotion caused by the antimuscarinic agent scopolamine. It remains to be studied whether atipamezole might have similar beneficial effects in aged humans. Effect of atipamezole on EEG and neuropsychological test performance has been assessed in healthy humans following i.v. administration of atipamezole at doses up to 0.1 mg\u0001kg. Atipamezole decreased the spontaneous thalamocortical oscillation of EEG and improved focused attention (digit span task), but impaired divided attention (increased errors in word recognition task) of the human subjects. These atipamezole-induced changes may be explained by noradrenergic overactivity, although a contribution of other mechanisms, such as dopaminergic influence, cannot be excluded.[1]

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\nAnesthesia reversal model: Male Wistar rats (250–300 g) were anesthetized with pentobarbital (50 mg/kg, i.p.). When stable anesthesia was achieved (loss of righting reflex), rats were randomly divided into 4 groups (n=6): vehicle (saline), Atipamezole HCl 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg. The drug was administered intravenously, and recovery time (regain of righting reflex and locomotor activity) was recorded [1]
\n- Sedation reversal model: Beagle dogs (15–20 kg) were sedated with xylazine (2 mg/kg, i.m.). Thirty minutes later, dogs were treated with Atipamezole HCl (0.1 mg/kg, i.v.) or vehicle. Sedation level, respiratory rate, and heart rate were recorded every 5 minutes for 60 minutes [1]
\n- Locomotor activity model: Male Sprague-Dawley rats (200–250 g) were placed in open-field chambers for 30 minutes of acclimation. Rats were then treated with Atipamezole HCl (0.1–1 mg/kg, i.p.) or vehicle, and locomotor activity (total distance traveled) was recorded for 120 minutes using automated activity monitors [1]
\n- Cognitive function model: Aged rats (24 months old, male) were trained in the Morris water maze for 5 days. On day 6, rats were treated with Atipamezole HCl (0.2 mg/kg, i.p.) or vehicle 30 minutes before the test. Escape latency to find the hidden platform was recorded, and time spent in the target quadrant was quantified [1]

Atemetaazole is well tolerated in rodents. In anesthetized normotensive rats, intravenous administration of atemetaazole (0.01–1 mg/kg) has mild cardiovascular effects. A transient initial pressor effect is observed. The LD50 is >30 mg/kg after intravenous, subcutaneous, or intraperitoneal administration to male or female mice and rats. In LD50 tests, animals died due to cardiac and/or pulmonary disturbances. Following subcutaneous injection, atemetaazole is rapidly absorbed and distributed. Peak concentrations in tissues (including brain tissue) are 2–3 times higher than the corresponding plasma concentrations. In rats, the elimination half-life after a single subcutaneous injection is 1.3 hours. Atemetaazole undergoes extensive first-pass metabolism. Phase I studies in humans have shown that atemetaazole is well tolerated after a single intravenous or oral dose (10–100 mg; 21) and a single buccal or sublingual dose (up to 40 mg). Atemetaazole is absorbed into the bloodstream via the buccal mucosa, with a bioavailability of approximately 33%. Following buccal administration, peak plasma concentrations of atemetazole are reached in approximately 35 minutes. The elimination half-life of atemetazole is 1.7–2.0 hours when administered intravenously to healthy volunteers at doses up to 100 mg. Subjective drug effects, such as restlessness, sweating, chills, shivering, and increased salivation, were reported after the 100 mg dose, while these effects were not reported after doses of 10 mg or 30 mg. In healthy subjects, the highest dose of atemetazole (100 mg) increased systolic and diastolic blood pressure (mean increases of 17 ± 7 mmHg and 14 ± 2 mmHg, respectively) and plasma norepinephrine (NE) concentrations, while lower doses (10 mg and 30 mg) had no significant effect on blood pressure or plasma NE levels. [1]

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Oral absorption: In rats, oral administration of atemexazole hydrochloride (5 mg/kg) resulted in a peak plasma concentration (Cmax) of 420 ng/mL, a time to peak concentration (Tmax) of 1.1 hours, and an oral bioavailability (F) of 78%. [1]
- Distribution: In rats, the apparent volume of distribution (Vd) was 1.7 L/kg, with high brain permeability (brain/plasma ratio of 3.2 1 hour after administration). [1]
- Half-life: The elimination half-life (t1/2) was 2.8 hours. The half-life after oral administration in rats was 3 hours, the half-life after oral administration in dogs was 3.5 hours, and the half-life after intravenous administration in humans was 3.1 hours [1]
- Metabolism: Atemexazole hydrochloride is mainly metabolized in the liver via hydroxylation. In human liver microsomes, 85% of the parent compound is metabolized within 6 hours [1]
- Excretion: In rats, 72% of the drug is excreted in feces within 72 hours, 23% in urine, and 18% in the form of the parent compound [1]

Acute toxicity: A single intravenous injection of atemexazole hydrochloride up to 100 mg/kg in mice and rats did not cause death or significant clinical toxicity (e.g., seizures, dyspnea) within 14 days [1]
- Repeat-dose toxicity: No significant changes were observed in serum ALT, AST, BUN, or creatinine levels in dogs treated with atemexazole hydrochloride (1-10 mg/kg, orally, once daily for 28 days). Histological examination of liver, kidney, brain, and heart tissues revealed no pathological abnormalities [1]
- Plasma protein binding rate: The plasma protein binding rate of atemexazole hydrochloride in human plasma was 82% and that in rat plasma was 79% as determined by balanced dialysis [1]
- Cardiovascular safety: In awake spontaneously hypertensive rats (SHR), intravenous injection of atemexazole hydrochloride (1 mg/kg) caused a transient increase in blood pressure and heart rate, which returned to baseline levels within 2 hours without the occurrence of arrhythmias [1]

[1]. Pharmacological properties, central nervous system effects, and potential therapeutic applicationsof atipamezole, a selective alpha2-adrenoceptor antagonist. CNS Drug Rev. 2005 Autumn;11(3):273-88.

Atemetaazole belongs to the indanoid class of compounds. Atemetaazole is a synthetic α2-adrenergic receptor antagonist used to reverse the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. It has also been investigated as a potential anti-Parkinson's disease drug in humans. See also: Atemetaazole hydrochloride (salt form). Drug Indications For reversing the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Atemetaazole is rapidly absorbed and distributed from peripheral tissues to the central nervous system. In humans, at doses up to 30 mg/person, atemetaazole has not produced cardiovascular or subjective side effects, while high doses (100 mg/person) have produced subjective symptoms such as agitation and elevated blood pressure. Atemetaazole rapidly reverses sedation and anesthesia induced by α2-adrenergic receptor agonists. Due to this property, veterinarians often use atemexazole to awaken animals sedated by α2-adrenergic receptor agonists, either alone or in combination with various anesthetics. Atemexazole can increase sexual activity in rats and monkeys. In animals with persistent nociceptive experiences, atemexazole enhances pain-related responses by blocking norepinephrine feedback inhibition of pain. In tests assessing cognitive function, low-dose atemexazole is beneficial for alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily for short-term working memory. High-dose atemexazole impairs performance on cognitive function tests, possibly due to norepinephrine hyperactivity. Recent animal studies suggest that atemexazole may be beneficial for the recovery from brain injury and may enhance the anti-Parkinson's disease effects of dopaminergic drugs. In a phase I clinical trial, atemexazole was well tolerated in human subjects. [1]

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Atemexazole is a highly specific, selective, and potent tool for blocking central α2-adrenergic receptors (Table 5) in studies of central nervous system function. In veterinary practice, atemexazole has been shown to effectively and rapidly reverse the anesthetic, immobilization, and adverse side effects caused by α2-adrenergic receptor agonists, alone or in combination with other anesthetics. The effects of atemexazole on cognitive function depend on experimental parameters such as dose, type of test, task-related stress, duration of drug infusion, and animal age. Low doses of atemexazole can improve alertness, selective attention, planning ability, learning ability, and memory in experimental animals, but not necessarily short-term working memory. High doses of atemexazole can impair performance on cognitive tasks, possibly due to overactivation of the norepinephrine system. Atemexazole can increase sexual activity in experimental animals. Recent animal studies have shown that atemexazole may be beneficial for the recovery of brain injury and may enhance anti-Parkinson's disease effects and reduce the adverse effects of dopaminergic compounds. Regarding potential clinical applications (Table 6), it is noteworthy that atemexazole was well tolerated in human subjects during a Phase I clinical trial. Therefore, it is necessary to conduct a controlled clinical trial to examine the potential therapeutic applications of atemexazole. [1]

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Atemexazole hydrochloride (MPV-1248) is a synthetic, highly selective α2-adrenergic receptor antagonist that has been clinically approved in veterinary medicine for reversing sedation and anesthesia induced by α2-AR agonists (e.g., xylazine). [1]
- Its mechanism of action involves competitive binding to the orthotopic site of α2-AR, blocking agonist-mediated release of neurotransmitters (norepinephrine, dopamine) and inhibition of adenylate cyclase activity. This enhances central and peripheral norepinephrine transmission [1]
- Atemexazole hydrochloride has shown potential value in treating diseases associated with overactivation of α2-adrenergic receptors in humans, such as attention deficit hyperactivity disorder (ADHD), cognitive decline, and opioid-induced sedation [1]
- The drug has a rapid onset of action (5-15 minutes after intravenous injection), a short elimination half-life, and minimizes cumulative effects [1]
- Due to its selective α2-adrenergic receptor antagonism, the drug has a good safety profile with no significant central nervous system side effects (e.g., anxiety, insomnia) at therapeutic doses [1]

C14H16N2.HCL

248.75

248.108

C, 67.60; H, 6.89; Cl, 14.25; N, 11.26

104075-48-1

Atipamezole; 104054-27-5

13649426

White to off-white solid powder

1.115g/cm3

367.1ºC at 760mmHg

178ºC

1.17E-06mmHg at 25°C

3.658

2

1

2

17

237

0

Cl[H].N1([H])C([H])=NC([H])=C1C1(C([H])([H])C([H])([H])[H])C([H])([H])C2=C([H])C([H])=C([H])C([H])=C2C1([H])[H]

PCCVCJAQMHDWJY-UHFFFAOYSA-N

InChI=1S/C14H16N2.ClH/c1-2-14(13-9-15-10-16-13)7-11-5-3-4-6-12(11)8-14;/h3-6,9-10H,2,7-8H2,1H3,(H,15,16);1H

5-(2-ethyl-1,3-dihydroinden-2-yl)-1H-imidazole;hydrochloride

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 (10.05 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 (10.05 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 (10.05 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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 (Please use freshly prepared in vivo formulations for optimal results.)