α adrenergic receptor; I1-Imidazoline receptor
Efaroxan HCl primarily targets α2-adrenoceptors (α2A, α2B, and α2C) and the imidazoline I1 receptor. It acts as a potent and highly selective antagonist at α2-adrenoceptors, with pKi values of 7.87, 7.42, and 5.74 for the α2A, α2B, and α2C subtypes, respectively. This high affinity for α2-adrenoceptors underlies its ability to block the effects of endogenous catecholamines and synthetic agonists at these receptors. Efaroxan HCl also binds to the I1 receptor with a pKi of 7.28, while its affinity for I2 receptors is low (pKi < 5). The compound's selectivity for α2-adrenoceptors over α1-adrenoceptors is exceptionally high, with a selectivity ratio (α2/α1) of 724. This selectivity is crucial for its pharmacological effects, as it allows for the specific modulation of α2-mediated pathways without significant interference with α1-mediated responses. In addition to its receptor binding, Efaroxan HCl promotes insulin secretion. This effect is mediated at a site distinct from I1 or I2 receptors, which has been termed the putative I3 receptor. The compound's ability to promote insulin secretion contributes to its antidiabetic activity. By blocking α2-adrenoceptors, Efaroxan HCl also antagonizes the hyperglycemic actions of α2-agonists, further contributing to its glucose-lowering effects. The compound's dual action on α2-adrenoceptors and imidazoline receptors, along with its insulinotropic effects, makes it a valuable tool for studying the complex interplay between these systems in the regulation of glucose homeostasis and cardiovascular function.

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].

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Efaroxan HCl exhibits potent in vitro activity as an antagonist at α2-adrenoceptors and as a ligand for imidazoline receptors. In radioligand binding assays using membrane preparations from bovine ventrolateral medulla, Efaroxan hydrochloride binds to α2-adrenergic and I1-imidazoline receptors with Ki values of 5.6 nM and 0.15 nM, respectively. This demonstrates its high affinity for both receptor types. In functional assays using isolated tissues, Efaroxan competitively antagonizes the inhibitory effects of p-aminoclonidine in the electrically stimulated rat vas deferens, with a pA2 value of 8.89, confirming its potent antagonism at prejunctional α2-adrenoceptors. It also antagonizes the contractile effects of phenylephrine on the rat anococcygeus muscle with a pA2 of 6.03, indicating its activity at α1-adrenoceptors, albeit with much lower potency. The selectivity ratio (α2/α1) for Efaroxan is 724, highlighting its exceptional preference for α2-adrenoceptors. In addition to its adrenergic activity, Efaroxan HCl promotes insulin secretion in vitro and in vivo. This insulinotropic effect is mediated through a site distinct from I1 or I2 receptors, known as the I3 receptor. These in vitro findings establish Efaroxan HCl as a highly potent and selective α2-adrenoceptor antagonist with additional imidazoline receptor binding and insulin-releasing properties.

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]

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Efaroxan HCl demonstrates significant in vivo activity, primarily related to its effects on glucose homeostasis and cardiovascular function. In conscious fasted rats, Efaroxan (1-5 mg/kg p.o.) has little effect on resting plasma glucose levels but markedly antagonizes the hyperglycemic actions of the α2-adrenoceptor agonist UK-14,304 and adrenaline. This indicates that Efaroxan can effectively block α2-adrenoceptor-mediated hyperglycemia in vivo. Furthermore, Efaroxan increases resting plasma insulin levels and markedly potentiates the rise in insulin levels produced by adrenaline. This insulinotropic effect is consistent with its ability to promote insulin secretion. The potentiation of adrenaline-induced insulin release is prevented by the co-administration of propranolol, suggesting that it may involve β-adrenoceptor-mediated mechanisms. In pithed rats, Efaroxan demonstrates its antagonist activity at both prejunctional and postjunctional α2-adrenoceptors. The intravenous doses of Efaroxan required to produce 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac α2-adrenoceptors and postjunctional vascular α2-adrenoceptors are 0.05 and 0.13 μmol/kg, respectively. In contrast, a much higher dose (2.96 μmol/kg) is needed to shift the curve for cirazoline at postjunctional vascular α1-adrenoceptors, confirming its α2-selectivity in vivo. These in vivo results demonstrate that Efaroxan HCl is a potent and selective α2-adrenoceptor antagonist that effectively modulates glucose and insulin levels in animal models.

The in vitro enzyme/receptor binding (non-cellular) assay for Efaroxan HCl typically involves assessing its affinity for α2-adrenoceptor subtypes and imidazoline receptors using radioligand binding techniques. In a typical protocol, membrane preparations from tissues or cells expressing the target receptors are incubated with a radiolabeled ligand (e.g., [3H]-rauwolscine for α2-adrenoceptors or [3H]-idazoxan for imidazoline receptors) and varying concentrations of Efaroxan HCl. After incubation, the bound and free radioligand are separated by filtration or centrifugation, and the radioactivity is measured. The displacement of the radioligand by Efaroxan HCl is used to calculate its binding affinity (Ki or pKi). For Efaroxan HCl, this method has been used to determine its pKi values of 7.87, 7.42, and 5.74 for the α2A, α2B, and α2C subtypes, respectively, and a pKi of 7.28 for the I1 receptor. These binding studies are critical for characterizing the compound's affinity, selectivity, and binding kinetics at its molecular targets.

The in vitro cellular assay for Efaroxan HCl typically involves evaluating its functional activity as an antagonist at α2-adrenoceptors and its effects on insulin secretion. For α2-adrenoceptor antagonism, functional assays using isolated tissues or cells are commonly employed. For example, the effect of Efaroxan on the electrically stimulated rat vas deferens is used to assess its antagonism of prejunctional α2-adrenoceptors, while its effect on phenylephrine-induced contraction of the rat anococcygeus muscle is used to assess α1-adrenoceptor antagonism. In these assays, the compound's ability to shift the dose-response curve of an agonist is measured to determine its potency (pA2). For studying insulin secretion, insulin-secreting cell lines such as RIN-5AH cells are used. These cells are treated with Efaroxan HCl, and the amount of insulin released into the medium is measured using an ELISA or a similar method. Efaroxan promotes insulin secretion in this assay, confirming its insulinotropic effect. These cellular assays provide functional evidence for Efaroxan HCl's activity as an α2-adrenoceptor antagonist and an insulin secretagogue.

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]

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The in vivo animal experimental protocol for Efaroxan HCl typically involves the use of rat models to assess its effects on glucose homeostasis and cardiovascular function. For studying its effects on glucose and insulin levels, conscious fasted rats are used. In a typical protocol, Efaroxan HCl is administered orally (p.o.) at doses ranging from 1 to 5 mg/kg. Blood samples are then collected at various time points to measure plasma glucose and insulin levels. The effect of Efaroxan on hyperglycemia induced by α2-adrenoceptor agonists such as UK-14,304 or adrenaline is also assessed. In these studies, rats are pretreated with Efaroxan, followed by administration of the agonist, and blood glucose levels are measured. For studying its cardiovascular effects, pithed rats are used, which allows for the selective evaluation of peripheral adrenoceptor function without central nervous system influences. In this model, Efaroxan is administered intravenously, and its ability to antagonize the effects of agonists at pre- and postjunctional α2-adrenoceptors is assessed. These in vivo models are essential for demonstrating the compound's pharmacological effects in a whole-organism context.

Efaroxan HCl is characterized as being orally bioactive. While specific pharmacokinetic (PK) parameters such as half-life, clearance, volume of distribution, or bioavailability are not detailed in the provided references, its oral activity is a key feature for its potential therapeutic use. The compound's ability to be absorbed and reach systemic circulation after oral administration is demonstrated by its effects on plasma glucose and insulin levels in conscious rats after oral dosing. The compound has a molecular weight of 252.74 and is stored at room temperature. It is soluble in DMSO and water. Further studies are needed to fully characterize the PK properties of Efaroxan HCl, including its absorption, distribution, metabolism, and excretion (ADME) profile.

Specific toxicity (toxicology) data for Efaroxan HCl, such as LD50 or results from repeat-dose toxicity studies, are not reported in the available literature. However, as a potent and selective α2-adrenoceptor antagonist, its toxicity profile would be expected to be related to its pharmacological activity. Potential adverse effects could include cardiovascular effects such as hypotension or tachycardia, as well as effects on the central nervous system. Comprehensive toxicological assessments, including acute and chronic toxicity studies, genotoxicity, and carcinogenicity, would be necessary to fully evaluate the safety profile of Efaroxan HCl for clinical development. The compound is for research use only and is not intended for human use.

[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.

Alpha-adrenergic receptor antagonists: These drugs bind to alpha-adrenergic receptors without activating them, thereby blocking the effects of endogenous or exogenous adrenergic agonists. Alpha-adrenergic receptor antagonists are used to treat hypertension, vasospasm, peripheral vascular disease, shock, and pheochromocytoma.

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Efaroxan HCl is also known as RX821037A and Efaroxan hydrochloride. Its chemical name is 2-(2-Ethyl-2,3-dihydro-2-benzofuranyl)-4,5-dihydro-1H-imidazole hydrochloride. The compound has a molecular weight of 252.74 and a purity of ≥99% (HPLC). It is a potent, highly selective α2-adrenoceptor antagonist and imidazoline I1 receptor ligand. Efaroxan HCl promotes insulin secretion at a site distinct from I1 or I2 (the putative I3 receptor) in vitro and in vivo. It is used in research for diabetes and cardiovascular diseases. The compound's high selectivity for α2-adrenoceptors over α1-adrenoceptors (ratio 724) makes it a valuable tool for studying α2-adrenoceptor function.

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

CCC1(CC2=CC=CC=C2O1)C3=NCCN3.Cl

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.)