Alpha 2-adrenoceptor

2-Methoxyidazoxan（RX 8210022）是一种高度选择性的α2-肾上腺素受体拮抗剂，几乎没有咪唑啉拮抗剂作用。RX821002是一种通过阻断蓝斑中的α2肾上腺素受体在皮质中引发去甲肾上腺素释放的药物[1]。

2-Methoxyidazoxan HCl/RX 821002(1 mg/kg) 可提高患有新生儿腹侧海马病变 (NVHL) 的大鼠在新环境中活动的能力。 2-2-甲基咪唑克单盐酸盐对运动的影响是双相的，首先表现出减弱，然后增强[3]。

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患有新生儿腹侧海马损伤（NVHL）的大鼠用于建立精神分裂症模型。它们在青春期后表现出更强的运动能力和学习困难。多巴胺能精神兴奋剂药物加强了这种行为改变，这也与精神分裂症有关，因为它说明了其多巴胺能方面。但只有多巴胺能药物才能产生这种作用，这仍然值得怀疑。行为效应可能只是代表一种非特异性的唤醒，在这种情况下，NVHL大鼠也应该对其他提高警惕的药物有高度反应。我们分别以5mg/kg和1mg/kg的剂量给药腺苷（咖啡因）或肾上腺素受体拮抗剂（RX 821002），以改变大鼠的警觉性。在实验前使用磁共振成像（MRI）选择大鼠。每组都有典型和相似的NVHL病变。将它们与假损伤大鼠进行比较。我们评估了在新环境中的运动能力，以及记忆宣布食物出现的视觉或听觉线索的能力。咖啡因和RX82100都能增强新环境中的运动能力，特别是在NVHL大鼠中。但是，RX82100对运动有双相影响，包括在增强之前的初始减少。它与病变无关。咖啡因不会改变NVHL大鼠的学习表现。但是，RX 821002被发现有助于学习。患者往往比健康人摄入更多的咖啡因，这被解释为一种对抗一些认知缺陷的方法。这一想法没有得到目前结果的验证。但肾上腺素能药物可能有助于减轻他们的一些认知缺陷[3]。

检查了四种拮抗剂区分α2A和直系α2D肾上腺素受体的能力。拮抗剂为（2S，12bS）1'，3'-二甲基螺环（1,3,4,5'，6,6'，7,12b-八氢-2H-苯并[b]呋喃并[2,3-a]喹啉嗪）-2,4'-嘧啶-2'-酮（MK912）、2-[2-（甲氧基-1,4-苯并二恶烷基）咪唑啉（RX 821002)依法氧嘧啶和苯氧噻嗪。兔大脑皮层中的α2受体被选为α2A，豚鼠大脑皮层中为α2D肾上腺素受体。大脑皮层切片用3H-去甲肾上腺素预孵育，然后用短暂的脉冲串（4个脉冲，100 Hz）进行超灌注和电刺激，即使有α2-自抑制作用，也很少。5-溴-6-（2-咪唑啉-2-基氨基）喹喔啉（UK 14304）用作α2-肾上腺素受体激动剂。UK 14304降低了刺激诱发的氚溢出。拮抗剂以明显竞争的方式将UK 14304的浓度抑制曲线向右移动。根据位移计算拮抗剂的解离常数。MK 912，RX 821002 依法沙星对（豚鼠）α2D肾上腺素受体的亲和力（pKd值分别为10.0、9.7和9.1）明显高于（兔）α2A肾上腺素受体（pKd分别为8.9、8.2和7.6）。苯氧噻嗪对α-2A-（pKd 7.4）的亲和力高于对α-2D肾上腺素受体（pKd 6.9）的亲和力。根据α2A和α2D之间的四种化合物的Kd值计算的比率高达100倍。结论是MK 912，RX 821002，依法氧嘧啶和苯氧噻嗪是具有高能力区分α2A和α2D肾上腺素受体的拮抗剂[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.

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.

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Increasing evidence indicates that the hypotensive effect of centrally acting antihypertensive drugs is not due to stimulation of alpha 2-adrenoceptors but to action on imidazoline receptors (IR). This has led to the development and recent clinical use of second generation agents such as rilmenidine and moxonidine that possess a much greater selectivity toward these nonadrenergic receptors. However, relatively few studies have examined the role of these receptors in conscious animals or have adequately accounted for the alpha 2-adrenoceptor antagonist properties of IR antagonists such as idazoxan. We have taken the approach of initially calibrating the alpha 2-adrenoceptor antagonist potency of intracisternally (ic) administered idazoxan and the IR-1 receptor antagonist efaroxan against 2-methoxyidazoxan, a highly selective alpha 2-adrenoceptor antagonist with little or no imidazoline antagonist effect. This was done using alpha-methyldopa, a hypotensive agent affecting only alpha 2-adrenoceptors. Thus, we chose doses of the antagonists with equal alpha 2-adrenoceptor blocking action such that differences in the ability of idazoxan or efaroxan compared to 2-methoxy-idazoxan to reverse the hypotension produced by rilmenidine, moxonidine, or clonidine indicate an interaction with IR. By this method we found that the hypotensive effects of rilmenidine and moxonidine at moderate intracisternal doses were more readily reversed by the imidazoline antagonists than by 2-methoxy-idazoxan, indicating that IR were largely responsible for their hypotensive actions. By contrast, clonidine's effects were equally reversed by all antagonists, suggesting interaction mainly with alpha 2-adrenoceptors. In conscious rabbits with chronic renal sympathetic nerve electrodes we examined the effect of rilmenidine and alpha-methyldopa on the renal sympathetic baroreflex. Both drugs reduced renal sympathetic nerve activity and sympathetic baroreflex responses, but only the effect of rilmenidine was preferentially reversed by idazoxan. Thus, both IR and central alpha 2-adrenoceptor receptors can influence the renal baroreflex, but the former are relatively more important for the actions of rilmenidine. We recently examined the possible sites of action of rilmenidine in anesthetized rabbits and showed that sixfold lower doses were required to reduce blood pressure when the drug was injected into the rostral ventrolateral medulla compared to intracisternal administration. At this site rilmenidine also reduced renal sympathetic tone and inhibited renal sympathetic baroreflex responses. By contrast, rilmenidine was relatively ineffective when injected into the nucleus of the solitary tract. These experiments support the view that rilmenidine acts primarily at IR in the rostral ventrolateral medulla to reduce sympathetic tone and modulate sympathetic baroreflexes.[1]

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Contrasting with the lack of improvement in the performance of rats under caffeine, RX821002, the alpha2-adrenoreceptor antagonist, improved learning. Research about the contribution of noradrenergic systems to schizophrenia has yielded inconsistent results (van Kammen and Antelman, 1984; van Kammen and Kelley, 1991; Yamamoto et al., 1994; Friedman et al., 1999; Klimek et al., 1999). Interest has been shown, however, in the prefrontal noradrenergic mechanisms and the potential role of alpha-2-adrenoreceptor antagonism in the antipsychotic effects of atypical neuroleptics, particularly considering that co-medication of fluphenazine with the alpha-2-adrenoreceptor antagonist idazoxan enhanced its antipsychotic and cognitive effectiveness (Litman et al., 1996). Our results complement these observations, highlighting the importance of adrenoreceptors as targets for treating cognitive difficulties like those experienced by 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

52.08

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

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

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)

配方 1 中的溶解度: 50 mg/mL (184.70 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
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10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
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