CB1 ( Ki = 1.8 nM )

Rimonabant is given intraperitoneally or orally to potently and dose-dependently oppose the traditional pharmacological and behavioral effects of cannabinoid receptor agonists. In the mouse model of azoxymethane-induced colon carcinogenesis, Rimonabant significantly decreased aberrant crypt foci (ACF) formation, which precedes colorectal cancer. Male obese Zucker rats, aged two weeks to three months, are fed rimonabant (10 mg/kg by gavage) as a model of impaired glucose tolerance; the rats, aged ten weeks to six months, are fed the drug as a model of the metabolic syndrome. The serum levels of MCP-1 (monocyte chemotactic protein-1) and RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) are higher in obese Zucker rats compared to lean Zucker rats. Long-term Rimonabant treatment significantly reduces these levels, slowing weight gain in rats with the metabolic syndrome. Rimonabant reduces neutrophils and monocytes, which are markedly elevated in young, old, obese Zucker rats compared to lean Zucker rats. Rimonabant reduces platelet-bound fibrinogen, which is significantly increased in obese compared to lean Zucker rats of both ages. Obese rats' platelets are more susceptible to adhesion to fibrinogen and thrombin-induced aggregation, both of which are lessened by rimonabant therapy.

Human CB1 and CB2 purify the cell membrane and transfect HEK 293 cells in a stable manner. In the incubation buffer (50 mM Tris-HCl, 5 mM MgCl2, 1 mM EDTA, 0.3% BSA, pH 7.4), 0.2–8 μg of the purified membrane are incubated with 0.75 nM [3H] CP55,940 and Rimonabant. In the presence of 1 μM of CP55,940, the non-specific binding is defined. The reactions are incubated in Multiscreen at 30 °C for one and a half hours. After four rounds of ice-cold wash buffer (50 mM Tris, pH 7.4, 0.25% BSA), the reactions are stopped by manifold filtration. With Topcount, the radioactivity bound to the filters is measured. The IC50 is computed using non-linear regression and is defined as the concentration of rimonabant needed to inhibit 50% of the binding of [3H] CP55,940.

Raw 264.7 after rinsing 12-well plates with PBS, cells (2 × 106/well) are refed with culture media supplemented with different amounts of Rimonabant one hour before 7-ketocholesterol (7KC) are added. The amount of vehicle is adjusted so that each well receives the same amount. A fluorogenic substrate (ac-DEVD-AFC) and a spectrofluorometer fitted with a microplate reader are used to measure caspase-3 and caspase 3-like activity after a 16-hour incubation.

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

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

Note: Please store this product in a sealed and protected environment, 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)

Solubility in Formulation 1: 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% Propylene glycol : 30 mg/mL

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