Alpha 2-adrenoceptor

2-methoxyidazoxan (RX 8210022) is a highly selective alpha 2-adrenoceptor antagonist with little or no imidazoline antagonist effect. RX821002 is a drug that elicits noradrenaline release in the cortex by blocking alpha2-adrenoautoreceptors in the locus coeruleus [1].

2-Methoxyidazoxan monohydrochloride/RX 821002 (1 mg/kg) improves the ability of rats with neonatal ventral hippocampal lesion (NVHL) to move about in new settings. 2-The effects of 2-methylidazoxan monohydrochloride on locomotion are biphasic, exhibiting a reduction at first before intensification [3].

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Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper-responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX 821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX 821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits[3].

Four antagonists were examined for their ability to differentiate alpha 2A-from the orthologous alpha 2D-adrenoceptors. The antagonists were (2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octah ydro-2H- benzo[b]furo[2,3-a]quinolizine)-2,4'-pyrimidin-2'-one (MK912), 2-[2-(methoxy-1,4-benzodioxanyl)imidazoline (RX 821002 ), efaroxan and benoxathian. The alpha 2-autoreceptors in rabbit brain cortex were chosen as alpha 2A-and the alpha 2-autoreceptors in guinea-pig brain cortex as alpha 2D-adrenoceptors. Slices of the brain cortex were preincubated with 3H-noradrenaline and then superfused and stimulated electrically by brief pulse trains (4 pulses, 100 Hz) that led to little, if any, alpha 2-autoinhibition. 5-Bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) was used as an alpha 2-adrenoceptor agonist. UK 14, 304 decreased the stimulation-evoked overflow of tritium. The antagonists shifted the concentration-inhibition curve of UK 14, 304 to the right in an apparently competitive manner. Dissociation constants of the antagonists were calculated from the shifts. MK 912, RX 821002 and efaroxan had markedly higher affinity for (guinea-pig) alpha 2D-adrenoceptors (pKd values 10.0, 9.7 and 9.1, respectively) than for (rabbit) alpha 2A-adrenoceptors (pKd 8.9, 8.2 and 7.6, respectively). Benoxathian had higher affinity for alpha 2A-(pKd 7.4) than for alpha 2D-adrenoceptors (pKd 6.9). Ratios calculated from the Kd values of the four compounds differentiated between alpha 2A and alpha 2D up to 100 fold. It is concluded that MK 912, RX 821002 , efaroxan and benoxathian are antagonists with high power to differentiate alpha 2A-from alpha 2D-adrenoceptors[2].

Selecting subjects using MRI imaging techniques[3]
Twenty-one day-old lesioned pups were subjected to an MRI session under isoflurane anesthesia. MRI was performed on a small-animal scanner operating at 4.7 T (TR/TE/TEeff: 3000/30 ms/60 ms). A series of 10 slices (256 × 256 pixels) was generated over a 1 cm long section of the brain, rostral to the cerebellum-cerebrum gap, as in our previous studies and those conducted by others (Angst et al., 2007; Macedo et al., 2008, 2010, 2012; Bertrand et al., 2010; Sandner et al., 2010, 2011, 2012), the purpose being to select triplets of lesioned rats (1 saline, 1 caffeine and 1 RX 821002), where each member of the triplet had about the same MRI image in terms of the location and symmetry of the lesion (examples are shown in Figure 1). We obtained 9 triplets of lesions (27 lesioned rats), to which we added 27 sham-lesioned controls. Rats that could not be included in a triplet were transferred to other research protocols.
Lesioned areas were drawn on MRI coronal sections. The numbers of pixels of the left and right lesions were summed up over successive rostro-caudal sections. The sum represents then the estimated volumes of the lesions. It was submitted to an ANOVA, with lesion side as within-group factor and treatment as between-group factor. Another ANOVA was computed on the sum of left and right lesions with the three rats in each triplet as within-group factor. The threshold for statistical significance for all statistical computations was set to p < 0.05.

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Treatments[3]
A 3 × 2 experimental design was used (6 groups of 9 rats). The treatment was applied before each test and each learning session. The latency between injection and the beginning of the test was 10 min for caffeine (5 mg/kg) and 20 min for RX 821002 (1 mg/kg), dissolved in saline (vehicle: veh) in a final volume of 1 ml and injected i.p. Control rats received a saline injection 10 or 20 min before testing. The following groups were considered: 9 NVHL rats treated with caffeine (caf group), 9 NVHL rats treated with RX 821002 (RX group), and 9 NVHL rats which were given saline (veh group), plus three groups of 9 sham-lesioned rats which received the same treatments.

[1]. Head GA. Importance of imidazoline receptors in the cardiovascular actions of centrally acting antihypertensive agents. Ann N Y Acad Sci. 1995;763:531-540.

[2]. Antagonists that differentiate between alpha 2A-and alpha 2D-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol. 1996;353(3):245-249.

[3]. Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion. Front Behav Neurosci. 2014;8:15. Published 2014 Jan 28.

Alpha-adrenergic receptor antagonists: These drugs bind to alpha-adrenergic receptors without activating them, thus 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. Increasing evidence suggests that the antihypertensive effect of centrally acting antihypertensive drugs is not due to stimulation of alpha-2 adrenergic receptors, but rather to action on imidazoline receptors (IR). This has led to the development and recent clinical application of second-generation drugs such as limenolide and mosoni, which exhibit higher selectivity for these non-adrenergic receptors. However, studies investigating the effects of these receptors in conscious animals are relatively few, and few studies fully explain the alpha-2 adrenergic receptor antagonistic properties of imidazoline receptor antagonists (such as idazoline). We first calibrated the α2-adrenergic receptor antagonistic efficacy of intracisional (IC) injection of idazoline and the IR-1 receptor antagonist efaroxa, using 2-methoxyidazoline (a highly selective IC antagonist with little imidazoline antagonism) as a control. Alpha-methyldopa, an antihypertensive drug that acts only on IC antagonists, was used in the calibration process. Therefore, we selected antagonist doses with similar IC blocking effects, such that the difference in the ability of idazoline or efaroxa to reverse hypotension induced by limenidine, moxonidine, or clonidine compared to 2-methoxyidazoline could indicate their interaction with the insulin receptor (IR). Using this method, we found that the antihypertensive effect of moderate-dose IC injection of limenidine and moxonidine was more easily reversed by imidazoline antagonists than by 2-methoxyidazoline, suggesting that the insulin receptor (IR) is the primary cause of their antihypertensive effect. In contrast, the effects of clonidine were reversible to the same extent by all antagonists, suggesting that it primarily interacts with α2-adrenergic receptors. In awake rabbits implanted with chronic renal sympathetic electrodes, we investigated the effects of limeridin and α-methyldopa on the renal sympathetic baroreflex. Both drugs reduced renal sympathetic activity and the baroreflex response, but only limeridin's effects were preferentially reversed by idazoline. Therefore, both insulin receptors and central α2-adrenergic receptors can affect the renal baroreflex, but the former is relatively more important for the effect of limeridin. We recently investigated the possible sites of action of limeridin in anesthetized rabbits, showing that injecting the drug into the ventrolateral anterior medulla oblongata reduced the required dose for blood pressure reduction by six-fold compared to intracisional administration. At this site, limeridin also reduced renal sympathetic tone and inhibited the renal sympathetic baroreflex. In contrast, the effect of limeridin injected into the nucleus tractus solitarius was relatively weak. These experiments support the view that limeridin mainly acts on the renal tubules in the anterior ventrolateral medulla, thereby reducing sympathetic tone and modulating the sympathetic baroreflex. [1] In contrast to caffeine, which has no effect on improving learning ability in rats, the α2-adrenergic receptor antagonist RX821002 can improve learning ability in rats. The results of studies on the contribution of the norepinephrine system to schizophrenia are inconsistent (van Kammen and Antelman, 1984; van Kammen and Kelley, 1991; Yamamoto et al., 1994; Friedman et al., 1999; Klimek et al., 1999). However, there has been considerable interest in the prefrontal noradrenergic mechanism and the potential role of α2-adrenergic receptor antagonism in the antipsychotic effects of atypical antipsychotics, especially given that the combination of fluphenazine and the α2-adrenergic receptor antagonist idazoline can enhance its antipsychotic and cognitive efficacy (Litman et al., 1996). Our findings complement these observations and highlight the importance of adrenergic receptors as targets for treating cognitive difficulties in patients with schizophrenia (McAllister, 2001; Masana et al., 2011). [3]

C12H15CLN2O3

270.71

270.077

C, 53.24; H, 5.59; Cl, 13.10; N, 10.35; O, 17.73

109544-45-8

109544-45-8 (HCl); 102575-24-6

11957683

White to off-white solid powder

1.368

2

4

2

18

321

0

IMPOOMVZVWKSAP-UHFFFAOYSA-N

InChI=1S/C12H14N2O3.ClH/c1-15-12(11-13-6-7-14-11)8-16-9-4-2-3-5-10(9)17-12;/h2-5H,6-8H2,1H3,(H,13,14);1H

2-(3-methoxy-2H-1,4-benzodioxin-3-yl)-4,5-dihydro-1H-imidazole;hydrochloride

RX 821002 hydrochloride; 109544-45-8; 2-(3-methoxy-2h-1,4-benzodioxin-3-yl)-4,5-dihydro-1h-imidazole,hydrochloride; 2-(2,3-DIHYDRO-2-METHOXY-1,4-BENZODIOXIN-2-YL)-4,5-DIHYDRO-1H-IMIDAZOLE HYDROCHLORIDE; 2-Methoxyidazoxan monohydrochloride; MFCD00069343; 2-(3-methoxy-2H-1,4-benzodioxin-3-yl)-4,5-dihydro-1H-imidazole;hydrochloride; 2-Methoxyidazoxan (monohydrochloride);

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 (e.g. under nitrogen), 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)

H2O: 100 mg/mL (369.40 mM)

Solubility in Formulation 1: 50 mg/mL (184.70 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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