BD 1047 dihydrobromide

Sigma 1 receptor

当给予 BD-1047（二氢溴酸盐）时，Cutamesine 可降低小鼠光感受器衍生的 661w 细胞因光照射而导致的细胞死亡率[2]。 Cutamesine 可降低 caspase 3/7 活性和线粒体损伤的升高水平，但 BD-1047（二氢溴酸盐）可减弱这种作用[2]。

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Cutamesine降低了661W细胞光暴露引起的细胞损伤[2]
我们检测了cutamesine是否保护661W细胞免受光诱导的细胞死亡。用cutamesine和/或BD-1047预处理的661W细胞的Hoechst 33342和PI染色的代表性照片如图1A所示。Hoechst 33342染色所有细胞（活的和死的），而PI只染色死的细胞。10 μM的cutamesine预处理对光诱导的细胞死亡具有保护作用（图1B），而在1 μM的sigma-1受体拮抗剂BD-1047处理后，保护作用明显消失（图1C）。

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Cutamesine对光暴露诱导的caspase-3/7激活有抑制作用[2]
为了研究cutamesine对光照诱导的caspase-3/7活化的影响，我们使用Caspase-Glo 3/7 Assay System检测caspase-3/7的活性。光照显著增加caspase-3/7活性（图4）。10 μM的Cutamesine显著降低了caspase 3/7的活化，而1 μM的BD-1047则减弱了这种作用（图4）。

BD-1047（二氢溴酸盐）（1-10 mg/kg；腹腔注射）剂量为 10 mg/kg 时，可减少阿朴吗啡 (APO) 诱导的小鼠攀爬行为[1]。 BD-1047（二氢溴酸盐）可以抵消普拉克索和舍曲林（但不是普拉克索和氟西汀）联合用药引起的抗抑郁样作用[3]。 ?二氢溴化物或 BD-1047 可逆转 Sig-1 R 激动剂在 NMDA 诱导的疼痛行为和 pNR1 免疫反应性中的增强作用，以及 pNR1 表达的增加[4]。

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sigma受体最初被归类为阿片受体的一个亚型，但后来发现它们是一个独特的药理实体。许多临床前和临床数据表明，西格玛受体配体与包括精神分裂症在内的神经精神疾病有关。大量数据表明sigma配体的潜在抗精神病活性来自于它们的“拮抗”活性。然而，sigma配体发挥其作用的亚细胞机制尚未被详细阐明，因此，术语“激动剂”或“拮抗剂”及其功能含义并不完全明确。本研究的目的是发现是否BD-1047，最近被描述为sigma受体的选择性功能拮抗剂，在动物模型中显示出抗精神病活性，预测精神分裂症的疗效。与临床证实具有抗精神病活性的两种选择性sigma配体rimcazole和panamesine相比，BD-1047并没有显著降低安非他明诱导的小鼠多动症。同样，它也不能改变NMDA受体拮抗剂、苯环利定、美金刚或二唑西平诱导的过度活跃。另一方面，bd1047减轻了阿帕吗啡引起的小鼠攀爬和苯环利定引起的大鼠头抽搐，就像利莫唑和帕那米辛一样。综上所述，BD-1047在本研究使用的模型中显示出中等活性，表明其作为抗精神病药物的有效性值得怀疑。然而，需要更详细的研究来明确证实这一结论。［1］

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黄体酮和BD-1047（一种sigma(1)受体拮抗剂）可抵消普拉克索和舍曲林（但普拉克索和氟西汀无效）联合给药引起的抗抑郁样作用。在该测试中，活跃的行为并没有反映出一般活动的增加，因为普拉克索和氟西汀或舍曲林的联合施用未能增强大鼠的运动活动。试验药物（SCH 23390、舒必利、s33084、WAY 100635、BD-1047和黄体酮）单独或与普拉克索、氟西汀或舍曲林合用均未改变运动活动。本研究结果表明，普拉克索与氟西汀或舍曲林合用可能比单独使用普拉克索具有更明显的抗抑郁活性，并且除了其他机制外，多巴胺D（2/3）和5-羟色胺（1A）受体可能有助于普拉克索与氟西汀或舍曲林在大鼠强迫游泳试验中的抗抑郁活性。此外，西格玛(1)受体可能是普拉米索和舍曲林在该试验中共同给药诱导抗抑郁样活性的可能机制之一。[3]

光诱导661W细胞死亡模型[2]
将661W细胞以每孔3 × 103个细胞的密度接种于96孔板中，在37℃5% CO2的湿化气氛下孵育24 h。然后用1 μM或10 μM的cutamesine和/或1 μM N-[2-（3,4-二氯苯基）乙基]-N-甲基-2-（二甲氨基）乙胺（BD-1047）二氢溴化物处理，在37℃5% CO2的湿化气氛下培养1 h。将细胞在含每种药物的2500勒克斯白色荧光灯下，在37℃5% CO2的湿化气氛下暴露24 h。暗对照细胞和光照射的661W细胞都来自同一种群，消除了任何先前存在的偏见（如光和温度），如Kanan等人（2007）所述。

Animal/Disease Models: Male Albino Swiss mice (50 days old, 25–28 g)[1]
Doses: 1 mg/kg, 3 mg/kg, 10 mg/kg
Route of Administration: intraperitoneal (ip)injection
Experimental Results: diminished the APO-induced climbing at the dose of 10 mg/kg in mice.

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Exposure to visible light [2]
The mice were kept in dark conditions for 24 h prior to light exposure for dark adaptation. The pupils of the mice were dilated using 1% cyclopentolate hydrochloride eye drops 30 min prior to exposure to light. The mice, which were not anesthetized, were exposed to visible light (8000 lux) emitted by white fluorescent lamps for 3 h in cages with reflective interiors. The temperature during exposure to light was maintained at 25 ± 1.5 °C. After the exposure to light, all of the mice were returned to darkness for 24 h and then kept under normal light/dark cycling conditions. Cutamesine (50 or 500 μM, injected volume; 2 μL), BD-1047 (500 μM), cutamesisne (500 μM) plus BD-1047 (500 μM), or PBS was injected into the intravitreal space 1 h prior to the light exposure. The concentrations of cutamesine in the vitreous body just after the intravitreal administration at 50 and 500 μM were estimated to be approximately 10 and 100 μM, respectively.

[1]. Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity. Pharmacol Rep. 2006 Sep-Oct;58(5):626-635.

[2]. Effect of a sigma-1 receptor agonist, cutamesine dihydrochloride (SA4503), on photoreceptor cell death against light-induced damage. Exp Eye Res. 2015 Mar;132:64-72.

[3]. Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Pharmacol Rep. 2006 Jul-Aug;58(4):493-500.

Next, we investigated the effect of cutamesine on the disruption of the mitochondrial membrane potential. Cutamesine recovered the disruption of the mitochondrial membrane potential, and BD-1047 inhibited this effect of cutamesine. These results suggest that cutamesine activated the sigma-1 receptor and enhanced its function to restore abnormal mitochondrial Ca2+ as well, as previously reported by another group (Tagashira et al., 2013). Therefore, the protective effect of cutamesine against light-induced damage might be dependent on recovering mitochondrial function. The activation of caspase-3, a cell death effector, was reported at the photoreceptors in retinal degeneration model animals (Jomary et al., 2001). Abnormal mitochondrial Ca2+ also mediates caspase-3 activation via cytochrome c release (He et al., 2000). In the present study, irradiation of white fluorescent light caused the caspase 3/7 activation in the 661W cells. Cutamesine reduced this elevated level, and this effect was prevented by BD-1047. These reports suggest that cutamesine inhibits caspase activity by recovering mitochondrial function.
Finally, we investigated the protective effect of cutamesine against light-induced damage in an in vivo murine model. The intravitreal injection of 50 and 500 μM of cutamesine suppressed the light-induced damage to retinal function and histological changes in mice. The concentrations of cutamesine in the vitreous body just after the intravitreal administration were estimated to be approximately 10 and 100 μM, respectively. The protective effect was similar to the effective concentration at 10 μM in vitro. Furthermore, the protective effect of cutamesine on the light-induced damage was eliminated by co-administration with BD-1047, a sigma-1 receptor antagonist. Therefore, this effect might depend on the activation of sigma-1 receptor protein, which leads to normalized mitochondrial function and the prevention of caspase activities, as in the present in vitro study. [2]

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The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD-1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD-1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Moreover, sigma(1) receptors may constitute one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in that test.[3]

C13H20CL2N2.2HBR

437.04

433.953

C, 35.73; H, 5.07; Br, 36.57; Cl, 16.22; N, 6.41

138356-21-5

138356-20-4; 138356-21-5 (HBr);

45073418

White to off-white solid powder

4.945

6.48

2

2

6

19

212

0

CN(C)CCN(C)CCC1=CC(=C(C=C1)Cl)Cl.Br.Br

WOALTFHGLDVJHK-UHFFFAOYSA-N

InChI=1S/C13H20Cl2N2.2BrH/c1-16(2)8-9-17(3)7-6-11-4-5-12(14)13(15)10-11;;/h4-5,10H,6-9H2,1-3H3;2*1H

N'-[2-(3,4-dichlorophenyl)ethyl]-N,N,N'-trimethylethane-1,2-diamine;dihydrobromide

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，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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (5.72 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (5.72 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: 33.33 mg/mL (76.26 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));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
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