α2 adrenergic receptor

[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.

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].

In 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
kg) 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
kg. 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]

---

i.v. injection of the drug; 100 microCi/animal, rat tail vein administration

Rats

Atipamezole is well tolerated in rodents. In anesthetized, normotensive rats, the cardiovascular effects of atipamezole (0.01–1 mg
kg, i.v.) are rather modest. An initial, shortlasting hypertensive effect can be detected. The LD50 is >30 mg
kg after i.v., s.c., or i.p. administration to male or female mice and rats. In the LD50 experiments, animals died due to cardiac and
or pulmonary disturbances. Following s.c. administration, atipamezole is rapidly absorbed and distributed. Peak concentrations in tissues, including the brain, are two- to three-fold higher than the corresponding plasma levels. In rat, the elimination half-life is 1.3 h after s.c. administration of a single dose. Atipamezole undergoes extensive first-pass metabolism. Phase I studies performed in humans indicate that atipamezole is well tolerated after a single i.v. or oral dose (10–100 mg; 21) as well as after single-dose buccal or sublingual administration (up to 40 mg). Atipamezole is absorbed from the buccal mucosa to circulation with a bioavailability of about 33%. The time to reach peak concentration of atipamezole in plasma is about ¾ hours following buccal administration to humans. When up to 100 mg of atipamezole was infused i.v. to healthy volunteers, the elimination half-life of the drug was 1.7–2.0 h. Subjective drug effects, such as motor restlessness, sweating, shivering, coldness and increased salivation, were reported after the dose of 100 mg, but not after doses of 10 mg or 30 mg. The highest atipamezole dose (100 mg) increased systolic and diastolic blood pressure (mean increases 17 ± 7 and 14 ± 2 mm Hg, respectively) and plasma NE concentration in healthy human subjects, while lower doses (10 and 30 mg) had no significant effects on the blood pressure or the plasma NE level.[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.

Atipamezole is a member of indanes.
Atipamezole is a synthetic α2 adrenoceptor antagonistused to reverse the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. It has also been undergone research as a potential anti-Parkinsonian drug for humans.
See also: Atipamezole Hydrochloride (has salt form).

---

Drug Indication
For the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs.

---

Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by alpha2-adrenoceptor agonists. Due to this property, atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by alpha2-adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, atipamezole increased pain-related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short-term working memory. At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.[1]

---

In the study of central nervous system functions, atipamezole provides a highly specific, selective and potent tool for blocking central á2-adrenoceptors (Table 5). In veterinary practice, atipamezole has proved useful in rapidly reversing the anesthesia, immobilization and undesirable side effects induced by á2-adrenoceptor agonists alone or in combination with other anesthetics. The effect of atipamezole on cognitive performance has varied depending on experimental parameters such as the dose, the type of test, stress related to the task, the duration of the drug infusion, and the age of the animal. At low doses, it has improved alertness, selective attention, planning, learning and recall of experimental animals, but not necessarily short-term working memory. At higher doses, atipamezole has impaired performance in cognitive tasks, probably due to overactivation of the noradrenergic system. Sexual activity of experimental animals was increased by atipamezole. Recent experimental animal studies suggest that atipamezole might have beneficial effects in recovery from brain damage and it also might enhance the anti-Parkinsonian effects and reduce adverse actions of dopaminergic compounds. Concerning potential clinical applications (Table 6), it is noteworthy that in phase I studies atipamezole has been well tolerated by human subjects. Thus, controlled clinical studies are warranted to test the potential therapeutic applications of atipamezole.[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.

---

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.

---

View More

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.

---

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