CB1 ( Ki = 1.8 nM )

体外活性：利莫那班剂量依赖性地降低 Raw264.7 巨噬细胞和分离的腹膜巨噬细胞中的 ACAT 活性，IC50 为 2.9 μM。 Rimonabant 在完整的 CHO-ACAT1 和 CHO-ACAT2 细胞以及无细胞测定中抑制 ACAT 活性，其抑制效率大致相同，对于 CHO-ACAT1 和 CHO-ACAT2 的 IC50 分别为 1.5 μM 和 2.2 μM。与 ACAT 抑制作用一致，利莫那班治疗可阻断巨噬细胞中 ACAT 依赖性过程、氧甾醇诱导的细胞凋亡和乙酰化 LDL 诱导的泡沫细胞形成。利莫那班以浓度依赖性方式拮抗大麻素受体激动剂对小鼠输精管收缩和大鼠脑膜腺苷酸环化酶活性的抑制作用。 Rimonabant 显着降低人结直肠癌细胞（DLD-1、CaCo-2 和 SW620）的细胞生长并诱导细胞死亡。利莫那班能够改变所有测试细胞系的细胞周期分布。特别是，利莫那班在 DLD-1 细胞中产生 G2/M 细胞周期停滞，而不诱导细胞凋亡或坏死。激酶测定：人CB1和CB2稳定转染HEK 293细胞并纯化细胞膜。将 0.2-8 μg 纯化膜与 0.75 nM [3H] CP55,940 和利莫那班在孵育缓冲液（50 mM Tris-HCl、5 mM MgCl2、1 mM EDTA、0.3%BSA，pH 7.4）中一起孵育。非特异性结合是在 1 μM CP55,940 存在的情况下定义的。反应在 Multiscreen 中于 30 °C 下孵育一个半小时。通过歧管过滤终止反应，并用冰冷的洗涤缓冲液（50mM Tris，pH 7.4，0.25% BSA）洗涤四次。通过 Topcount 测量与过滤器结合的放射性。 IC50确定为抑制50%[3H]CP55,940结合所需的利莫那班浓度，并通过非线性回归计算。细胞测定：在补充 7-酮胆固醇 (7KC) 之前 1 小时，用 PBS 冲洗 12 孔板中的原始 264.7 细胞（2 × 106 个/孔），并重新添加不同量利莫那班的培养基。所有井均经过调整以接收等量的车辆。孵育 16 小时后，使用荧光底物 (Ac-DEVD-AFC) 和配备酶标仪的分光荧光计测定 caspase-3 和 caspase 3 样活性。

利莫那班通过腹膜内或口服给药，可有效拮抗大麻素受体激动剂的经典药理学和行为效应，并呈剂量依赖性。在氧化偶氮甲烷诱导的结肠癌小鼠模型中，利莫那班显着减少了异常隐窝灶（ACF）的形成，而异常隐窝灶（ACF）的形成先于结直肠癌。将利莫那班（10 mg/kg，灌胃）喂给 3 个月大的雄性肥胖 Zucker 大鼠 2 周作为糖耐量受损模型，喂给 6 个月大的雄性肥胖 Zucker 大鼠 10 周作为代谢模型。综合症。与瘦 Zucker 大鼠相比，肥胖 Zucker 大鼠的 RANTES（受激活、正常 T 细胞表达和分泌调节）和 MCP-1（单核细胞趋化蛋白-1）血清水平升高，长期使用利莫那班治疗可显着降低，从而减缓体重增加患有代谢综合征的老鼠。与瘦 Zucker 大鼠相比，年轻和年老肥胖大鼠的中性粒细胞和单核细胞显着增加，而利莫那班则降低。在两个年龄的肥胖 Zucker 大鼠中，血小板结合纤维蛋白原均显着增强，而利莫那班则降低。肥胖大鼠的血小板对凝血酶诱导的聚集和纤维蛋白原粘附更敏感，利莫那班治疗可减弱这两种情况。

人CB1和CB2纯化细胞膜并稳定转染HEK 293细胞。在孵育缓冲液（50 mM Tris-HCl、5 mM MgCl2、1 mM EDTA、0.3% BSA，pH 7.4）中，将 0.2–8 μg 纯化膜与 0.75 nM [3H] CP55,940 和利莫那班一起孵育。在 1 μM CP55,940 存在的情况下，定义了非特异性结合。反应在 Multiscreen 中于 30 °C 下孵育一个半小时。四轮冰冷洗涤缓冲液（50 mM Tris，pH 7.4，0.25% BSA）后，通过歧管过滤停止反应。使用 Topcount，可以测量与过滤器结合的放射性。使用非线性回归计算IC50，并将其定义为抑制50%[3H]CP55,940结合所需的利莫那班浓度。

Raw 264.7 用 PBS 冲洗 12 孔板后，将细胞（2 × 106/孔）重新加入添加了不同量利莫那班的培养基中，然后添加 7-酮胆固醇 (7KC) 一小时。调整载体的量，使得每口井接收相同的量。孵育 16 小时后，使用荧光底物 (ac-DEVD-AFC) 和配有酶标仪的分光荧光计来测量 caspase-3 和 caspase 3 样活性。

Adolescent exposure to cannabinoids enhances the behavioural effects of cocaine, and high novelty-seeking trait predicts greater sensitivity to the conditioned place preference (CPP) induced by this drug. Our aim was to evaluate the influence of novelty-seeking on the effects of adolescent cannabinoid exposure. Adolescent male mice were classified as high or low novelty seekers (HNS and LNS) in the hole-board test. First, we evaluated the CPP induced by the cannabinoid agonist WIN 55212-2 (0.05 and 0.075 mg/kg, i.p.) in HNS and LNS mice. Then, HNS and LNS mice were pretreated i.p. with vehicle, WIN 55212-2 (0.1 mg/kg), or cannabinoid antagonist rimonabant (1 mg/kg) and were subsequently conditioned with WIN 55212-2 (0.05 mg/kg, i.p.) or cocaine (1 or 6 mg/kg, i.p.). Only HNS mice conditioned with the 0.075 mg/kg dose acquired CPP with WIN 55212-2. Adolescent exposure to this cannabinoid agonist increased the rewarding effects of 1 mg/kg of cocaine in both HNS and LNS mice, and in HNS mice it also increased the reinstating effect of a low dose of cocaine. Our results endorse a role for individual differences such as a higher propensity for sensation-seeking in the development of addiction.[3]

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Dissolved in two drops of Tween 80, diluted in distilled water; 20 ml/kg (mice) and 5 ml/kg (rats); i.p. injection

Male mice and male rats

Absorption, Distribution and Excretion
Undetermined

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Metabolism / Metabolites
Hepatic, CYP3A4 involved.

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Biological Half-Life
6 to 9 days with normal BMI and 16 days if BMI is greater than 30

Protein Binding
Almost 100%

[1]. FEBS Lett. 1994 Aug 22;350(2-3):240-4.

[2]. FInt J Cancer. 2009 Sep 1;125(5):996-1003.

[3]. Neural Plast. 2016;2016:6481862.

Rimonabant is a carbohydrazide obtained by formal condensation of the carboxy group of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid with the amino group of 1-aminopiperidine. It is a potent and selective cannabinoid receptor 1 (CB1R) antagonist. Besides its antagonistic properties, numerous studies have shown that, at micromolar concentrations rimonabant behaves as an inverse agonist at CB1 receptors. The drug was the first selective CB1 antagonist/inverse agonist introduced into clinical practice to treat obesity and metabolic-related disorders. It was later withdrawn from market due to CNS-related adverse effects including depression and suicidal ideation. It has a role as an anti-obesity agent, a CB1 receptor antagonist and an appetite depressant. It is a member of pyrazoles, a dichlorobenzene, a carbohydrazide, an amidopiperidine and a member of monochlorobenzenes.
Rimonabant is an anorectic anti-obesity drug produced and marketed by Sanofi-Aventis. It is an inverse agonist for the cannabinoid receptor CB1. Its main avenue of effect is reduction in appetite. Rimonabant is the first selective CB1 receptor blocker to be approved for use anywhere in the world. Rimonabant is approved in 38 countries including the E.U., Mexico, and Brazil. It was rejected for approval for use in the United States. This decision was made after a U.S. advisory panel recommended the medicine not be approved because it may increase suicidal thinking and depression.
A pyrazole and piperidine derivative that acts as a selective cannabinoid type-1 receptor (CB1 RECEPTOR) antagonist. It inhibits the proliferation and maturation of ADIPOCYTES, improves lipid and glucose metabolism, and regulates food intake and energy balance. It is used in the management of OBESITY.

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Drug Indication
For use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m2, or patients wih a BMI greater than 27 kg/m2 with associated risk factors, such as type 2 diabetes or dyslipidaemia.
As an adjunct to diet and exercise for the treatment of obese patients (BMI 30 kg/m2), or overweight patients (BMI 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia (see section 5. 1).
As an adjunct to diet and exercise for the treatment of obese patients (BMI 30 kg/m2), or overweight patients (BMI 27 kg/m2) with associated risk factor(s), such as type 2 diabetes or dyslipidaemia (see section 5. 1).

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Mechanism of Action
Rimonabant is a specific CB1 cannabinoid receptor antagonist. There is considerable evidence that the endocannabinoid (endogenous cannabinoid) system plays a significant role in appetitive drive and associated behaviours. It is therefore reasonable to hypothesize that the attenuation of the activity of this system would have therapeutic benefit in treating disorders that might have a component of excess appetitive drive or over-activity of the endocannabinoid system, such as obesity, ethanol and other drug abuse, and a variety of central nervous system and other disorders.

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Pharmacodynamics
In the RIO-North America trial, 3040 patients were randomized to receive either placebo or one of two doses of rimonabant (5 mg or 20 mg per day). Patients taking 20 mg rimonabant had significant weigh loss, decrease in waist circumference, improved insulin sensitivity, and increases in HDL cholesterol, compared to patients on placebo.

C22H22CL4N4O

500.25

498.054

C, 52.82; H, 4.43; Cl, 28.35; N, 11.20; O, 3.20

158681-13-1

Rimonabant; 168273-06-1; Rimonabant-d10 hydrochloride; 1044909-61-6

104850

White to off-white solid powder

627.6ºC at 760 mmHg

230-240ºC

333.3ºC

7.069

50.16

1

3

4

30

583

0

ClC1C([H])=C(C([H])=C([H])C=1N1C(C2C([H])=C([H])C(=C([H])C=2[H])Cl)=C(C([H])([H])[H])C(C(N([H])N2C([H])([H])C([H])([H])C([H])([H])C([H])([H])C2([H])[H])=O)=N1)Cl.Cl[H]

REOYOKXLUFHOBV-UHFFFAOYSA-N

InChI=1S/C22H21Cl3N4O.ClH/c1-14-20(22(30)27-28-11-3-2-4-12-28)26-29(19-10-9-17(24)13-18(19)25)21(14)15-5-7-16(23)8-6-15;/h5-10,13H,2-4,11-12H2,1H3,(H,27,30);1H

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-piperidin-1-ylpyrazole-3-carboxamide;hydrochloride

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 (5.00 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), 悬浮液；超声助溶。
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 (5.00 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (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 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL

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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。