BD1063 HCl

Sigma-1 receptor (Sig-1R) antagonist. BD-1063 has preferential, nanomolar affinity for Sig-1Rs and is 30-fold selective for Sig-1R versus Sig-2R sites.[1]

本研究不包含经典的体外药理活性实验（如抗增殖、酶抑制）。主要的体外成分是基因表达的定量 PCR 分析。[1]
定量实时 PCR 显示，与未接触乙醇的近交系 Wistar 对照组相比，未接触乙醇的撒丁岛酒精偏好 (sP) 大鼠和戒断 24 小时的乙醇依赖 Wistar 大鼠的伏隔核中 Sig-1R mRNA 水平显著降低。在腹侧被盖区、中央杏仁核或基底外侧杏仁核中未观察到显著差异。[1]

在不改变非依赖性 Wistar 对照中平均乙醇自我给药的剂量下，BD1063 剂量依赖性地减少 sP 大鼠 (3.3-11 mg/kg) 和退缩、依赖性 Wistar 大鼠 (4 -11毫克/千克）。此外，BD1063 降低了 sP 大鼠在强化计划中以渐进比例进行乙醇劳动的断点[1]。在可口大鼠中，BD1063 以剂量依赖的方式抑制进食率升高并减少暴饮暴食以及食物反应的规律性。在不影响运动活动的情况下，BD1063 既可以阻止可口食物的消耗增加，也可以阻止光/暗冲突测试中在不愉快的隔间中度过更长的时间[2]。在 WT 小鼠中，每次紫杉醇治疗前半小时给予 BD1063，以防止机械性异常性疼痛和冷性异常性疼痛的发生。此外，两种形式的紫杉醇引起的异常性疼痛均可通过急性剂量依赖性注射 BD1063 来逆转[3]。

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皮下注射 BD-1063 在两种过度饮酒动物模型中剂量依赖性地减少操作性口服乙醇自我给药：1) 急性戒断的乙醇依赖 Wistar 大鼠 (4-11 mg/kg)；2) 基因选择的撒丁岛酒精偏好 (sP) 大鼠 (3.3-11 mg/kg)。高达 11 mg/kg 的剂量不会显著改变非依赖 Wistar 对照大鼠的平均乙醇自我给药量。[1]
BD-1063 (4.4-11 mg/kg) 降低了 sP 大鼠在渐进比率强化程序下对乙醇的断点，表明其为获取乙醇而付出努力的动机降低。[1]
该效应具有选择性，针对乙醇强化。BD-1063 不会减少并发的饮水自我给药，也不会同等程度地抑制 Wistar 或 sP 大鼠对具有同等强化效应的糖精溶液的自我给药。[1]
测试的最高剂量 (11 mg/kg, 皮下注射) 使依赖型 Wistar 大鼠的固定比率操作性乙醇反应减少 37%，使 sP 大鼠减少 42%。[1]

Sigma-1 受体亲和力与竞争性放射性配体结合实验: 从全脑制备粗突触体膜 (P2组分)。膜样品解冻后重悬于孵育缓冲液 (50 mM Tris-HCl， pH 8.0) 中。对于竞争实验，膜与固定浓度 (5 nM) 的 σ1 受体放射性配体 [³H](+)-pentazocine 以及浓度递增 (10⁻¹⁰ 至 10⁻⁵ M) 的未标记 BD-1063 或其溶剂在30°C下孵育240分钟。非特异性结合在10 μM 氟哌啶醇存在下定义。通过加入冰冷过滤缓冲液终止反应，结合放射性通过经聚乙烯亚胺预浸泡的玻璃纤维滤膜进行快速真空过滤分离。滤膜结合放射性通过液体闪烁计数定量。IC50 和 Ki 值根据抑制曲线确定。[3]
竞争性相互作用的饱和结合实验: 在不存在和存在固定、接近 IC50 浓度的未标记 BD-1063 (12.5 nM) 条件下，生成 [³H](+)-pentazocine (0.06–33 nM) 的饱和结合等温线。膜按上述方法孵育。KD 和 Bmax 值通过饱和曲线的非线性回归分析确定。在 BD-1063 存在下 KD 显著增加而 Bmax 不变表明其为竞争性拮抗作用。[3]

Rats: BD-1063 HCl (BD1063 hydrochloride) is solubilized in isotonic saline and injected subcutaneously (s.c. 1 ml/kg), 15 min before testing. Rats are pretreated with BD1063 (0, 4.4, 7 and 11 mg/kg of body weight, free base weights, s.c.) using a within-subject Latin square design. sP rats: Rats are pretreated with BD1063 (0, 3, 4.4, 7 and 11 mg/kg of body weight, free base basis, s.c.) using a within-subject Latin square design[1].

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Ethanol Self-Administration in Rats: Male Wistar and Sardinian alcohol-preferring (sP) rats were used. For operant training, rats pressed a lever on a fixed-ratio 1 schedule to receive 0.1 ml of 10% (v/v) ethanol solution during daily sessions (30-min for Wistar, 60-min for sP).
Drug Treatment: BD-1063 was solubilized in isotonic saline and administered subcutaneously at a volume of 1 mL/kg, 15 minutes before the behavioral testing session. Doses tested were based on the free base weight: 0, 4.4, 7, 11 mg/kg for Wistar rats; 0, 3, 4.4, 7, 11 mg/kg for sP rats. A within-subject Latin square design was used.[1]
Ethanol Dependence Model: Wistar rats were made ethanol-dependent via intermittent exposure to ethanol vapor (14 hours on/10 hours off daily for 6 weeks), achieving target blood alcohol levels of 150-200 mg%. Operant testing began 6 hours after vapor offset during acute withdrawal.[1]
Progressive-Ratio Schedule: sP rats were trained to self-administer ethanol under a progressive-ratio schedule where the response requirement increased exponentially. The session ended when no response occurred for 15 minutes. Breakpoint was defined as the last ratio completed.[1]
Saccharin Control: To assess specificity, separate groups of rats were trained to self-administer a saccharin solution (concentration adjusted to match baseline response rates for ethanol) under an FR1 schedule, followed by BD-1063 pretreatment.[1]

It is noted that previous reports showed a lack of locomotor suppressant effects for BD-1063 and the related compound BD-1047 at doses up to 30 mg/kg, arguing against general behavioral suppression or acute toxicity at the tested doses.[1]

[1]. The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology. 2009 May;34(6):1482-93.

[2]. Antagonism of sigma-1 receptors blocks compulsive-like eating. Neuropsychopharmacology. 2012 Nov;37(12):2593-604.

[3]. Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice. J Pain. 2012 Nov;13(11):1107-21.

1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine is a primary amine.

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BD-1063 is a potent and selective sigma-1 receptor (Sig-1R) antagonist. Sigma receptors have been implicated in the behavioral effects of psychostimulants. This study suggests that Sig-1R systems may contribute to excessive ethanol intake and reinforcement, identifying them as a potential therapeutic target for alcohol abuse and dependence.[1]
The reduced Sig-1R mRNA expression in the nucleus accumbens of both ethanol-naïve sP rats and withdrawn dependent rats suggests a potential neuroadaptive mechanism, which may be related to an innate or ethanol-induced increased susceptibility to high ethanol intake.[1]
The mechanism by which Sig-1R antagonism reduces ethanol reinforcement may involve indirect modulation of dopaminergic transmission within the mesolimbic pathway and/or interference with intracellular calcium signaling associated with the endoplasmic reticulum.[1]

C13H18N2CL2.2[HCL]

346.1233

344.038

206996-13-6

Related CAS 206996-13-6 (HCl); 150208-28-9

574780

White to off-white solid powder

4.263

6.48

0

2

3

17

230

0

NXFDBTLQOARIMH-UHFFFAOYSA-N

InChI=1S/C13H18Cl2N2.2ClH/c1-16-6-8-17(9-7-16)5-4-11-2-3-12(14)13(15)10-11;;/h2-3,10H,4-9H2,1H3;2*1H

1-[2-(3,4-dichlorophenyl)ethyl]-4-methyl-piperazine, dihydrochloride

BD1063; BD 1063; BD-1063;

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)

H2O : ~100 mg/mL (~288.92 mM)

配方 1 中的溶解度: 100 mg/mL (288.92 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;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。