α adrenergic receptor; I1-Imidazoline receptor

Efaroxan hydrochloride binds to α2-adrenergic and I1-imidazoline receptors in the ventrolateral medullary membrane of cattle, with a Kis of 5.6 nM and 0.15 nM, respectively[1].

Efaroxan hydrochloride enhances plasma insulin levels in awake fed and fasted rats without significantly influencing plasma glucose levels [3].

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The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha 2/alpha 1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mumol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha 2-adrenoceptors and postjunctional vascular alpha 2-adrenoceptors, and for cirazoline at postjunctional vascular alpha 1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha 2-adrenoceptor antagonist and provide further support for the involvement of alpha 2-adrenoceptors in glucose homeostasis.[1]

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The effect of alpha-2 adrenoceptor antagonists, yohimbine and efaroxan, on the plasma glucose and insulin levels was studied in non-diabetic control, type-I (insulin-dependent) and type-II (non-insulin-dependent) diabetic rats. Pretreatment with either yohimbine or efaroxan potentiated glucose-induced insulin release in non-diabetic control rats and produced an improvement of the oral glucose tolerance and potentiated glucose-induced insulin release in type-II but not in type-I diabetic rats. Treatment with either yohimbine or efaroxan reduced the plasma glucose level and increased the plasma insulin level of non-diabetic control and type-II diabetic rats but not of type-I diabetic rats. Effects of efaroxan were more marked. Pretreatment of non-diabetic control and type-II diabetic rats with either yohimbine or efaroxan inhibited clonidine-induced hyperglycaemia and suppressed or reversed clonidine-induced hypoinsulinaemia. Also, pretreatment of these animals with either yohimbine or efaroxan enhanced the hypoglycaemic and insulinotropic effects of glibenclamide. The combination of glibenclamide and efaroxan led to a synergistic increase in insulin secretion, while that of glibenclamide and yohimbine led to an additive increase. The hyperglycaemic effect of diazoxide in non-diabetic control and type-II diabetic rats was inhibited by pretreatment with either yohimbine or efaroxan. The hypoinsulinaemic effect of diazoxide in these animals was antagonized and reversed by pretreatment with yohimbine and efaroxan, respectively. In type-I diabetic rats, there was no change in the plasma glucose and insulin levels induced by the treatment of animals with each of clonidine or diazoxide alone or in combination with either yohimbine or efaroxan. Glibenclamide produced a slight decrease in the plasma glucose level of type-I diabetic rats, at the end of the 120 min period of investigation but there was no change in the plasma insulin level. Pretreatment of these animals with either yohimbine or efaroxan produced no change in glibenclamide effects. Additionally, bath application of efaroxan or glibenclamide inhibited the relaxant effects of different concentrations of diazoxide on the isolated norepinephrine-contracted aortic strips, while the application of yohimbine produced insignificant changes. The combination of glibenclamide and efaroxan led to complete inhibition of the relaxant effects of different concentrations of diazoxide, while that of glibenclamide and yohimbine did not produce such an effect. It is concluded that yohimbine, via blockade of postsynaptic alpha-2 adrenoceptors, and efaroxan, via blockade of postsynaptic alpha-2 adrenoceptors and adenosine triphosphate-sensitive potassium channels in the pancreatic beta-cell membrane, produce insulinotropic and subsequent hypoglycaemic effects.[2]

Animal/Disease Models: Male SD (SD (Sprague-Dawley)) rats (weight range 250-300g) [3]
Doses: 1 mg/kg, 5 mg/kg
Route of Administration: Oral
Experimental Results: Plasma insulin levels were Dramatically increased in starved rats at 15 and 30 minutes After treatment.

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The effect of Efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.o.; a standard sulphonylurea) on basal plasma glucose levels of fed and fasted rats. In addition, the effect of efaroxan (5 mg/kg p.o.) and glibenclamide (2 or 5 mg/kg p.o.), alone and in combination, on the hyperglycaemia and hyperinsulinaemia induced by glucose challenges, were investigated. An intra-arterial (250 mg/kg i.a.) and a subcutaneous (1 g/kg s.c.) glucose challenge were used to stimulate the fast and slow release phases of insulin secretion. Efaroxan increased plasma insulin levels in both conscious fed and fasted rats without greatly affecting plasma glucose levels. Glibenclamide also elevated insulin levels, but was associated with marked hypoglycaemia. Efaroxan and glibenclamide potentiated the slow and fast release of insulin secretion, but glibenclamide had a tendency to produce hypoglycaemia in these test situations, a property not shared by efaroxan. A combination of efaroxan and glibenclamide produced a greater elevation in the slow and fast insulin release phases than either compound alone, but did not enhance the hypoglycaemia seen with glibenclamide alone. These results provide further evidence that pancreatic alpha 2-adrenoceptors are involved in the regulation of insulin secretion.[3]

[1]. Selectivity profile of the alpha 2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat. Eur J Pharmacol. 1992 Mar 24;213(2):205-12.

[2]. Selectivity profile of the alpha 2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat. Eur J Pharmacol. 1992 Mar 24;213(2):205-12.

[3]. The potential antidiabetic activity of some alpha-2 adrenoceptor antagonists. Pharmacol Res. 2001 Nov;44(5):397-409.

[4]. Comparison of the effects of efaroxan and glibenclamide on plasma glucose and insulin levels in rats. Eur J Pharmacol. 1992 Mar 24;213(2):213-8.

Adrenergic alpha-Antagonists: Drugs that bind to but do not activate alpha-adrenergic receptors thereby blocking the actions of endogenous or exogenous adrenergic agonists. Adrenergic alpha-antagonists are used in the treatment of hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma.

C13H17CLN2O

252.74

252.102

C, 61.78; H, 6.78; Cl, 14.03; N, 11.08; O, 6.33

89197-00-2

11957548

White to off-white solid powder

387ºC at 760 mmHg

187.9ºC

2.338

2

2

2

17

302

0

DWOIUCRHVWIHAH-UHFFFAOYSA-N

InChI=1S/C13H16N2O.ClH/c1-2-13(12-14-7-8-15-12)9-10-5-3-4-6-11(10)16-13;/h3-6H,2,7-9H2,1H3,(H,14,15);1H

2-(2-ethyl-3H-1-benzofuran-2-yl)-4,5-dihydro-1H-imidazole;hydrochloride

RX821037A; RX 821037A; 89197-32-0; RX-821037A; Efaroxano; Efaroxanum; Efaroxanum [INN-Latin]; Efaroxano [INN-Spanish]; Efaroxan [INN:BAN]; 2-(2-ethyl-3H-1-benzofuran-2-yl)-4,5-dihydro-1H-imidazole; Efaroxan HCl

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)

DMSO : ~50 mg/mL (~197.83 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.89 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 (9.89 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 (9.89 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.)