CB1 ( Ki = 1.8 nM )
Rimonabant HCl (SR141716) targets the central cannabinoid receptor (CB1 receptor) with nanomolar affinity; it shows no activity on the peripheral cannabinoid receptor. [1]

Rimonabant HCl (SR141716) acts as a selective antagonist of the CB1 receptor. [2]

In vitro activity: Rimonabant decreases ACAT activity in isolated peritoneal macrophages and Raw264.7 macrophages in a dose-dependent manner with an IC50 of 2.9 μM. Rimonabant exhibits nearly equal efficacy in inhibiting ACATactivity in both intact CHO-ACAT1 and CHO-ACAT2 cells as well as in cell-free assays with IC50 of 1.5 μM and 2.2 μM for CHO-ACAT1 and CHO-ACAT2, respectively. Rimonabant treatment inhibits ACAT-dependent processes in macrophages, such as acetylated-LDL-induced foam cell formation and oxysterol-induced apoptosis, which is consistent with ACAT inhibition. In a concentration-dependent manner, rimonabant counteracts the inhibitory effects of cannabinoid receptor agonists on rat brain membrane adenylyl cyclase activity and mouse vas deferens contractions. Human colorectal cancer cell lines (DLD-1, CaCo-2, and SW620) exhibit markedly reduced cell proliferation and induced cell death in response to ridonabant. In every cell line tested, rimonabant can change the distribution of the cell cycle. Specifically, in DLD-1 cells, rimonabant causes a G2/M cell cycle arrest without causing necrosis or apoptosis.

---

1. Rimonabant HCl (SR141716) antagonizes the inhibitory effects of cannabinoid receptor agonists on contractions of mouse vas deferens and on adenylyl cyclase activity in rat brain membranes. [1]

2. Rimonabant HCl (SR141716) exerts significant antitumor effects on human colorectal cancer cell lines (DLD-1, CaCo-2, and SW620): it markedly reduces cell growth, induces cell death, and alters cell cycle distribution in all tested cell lines. Specifically, in DLD-1 cells, it causes G2/M cell cycle arrest without inducing apoptosis or necrosis. This G2/M arrest is accompanied by an increased mitotic index, as well as elevated DNA double-strand breaks and chromosome misjoining events—hallmarks of mitotic catastrophe. Protein expression analysis via western blot demonstrates that the induced mitotic catastrophe is mediated by interference with the spindle assembly checkpoint and the DNA damage checkpoint, as evidenced by changes in the expression of Cyclin B1, PARP-1, Aurora B, and phosphorylated p38/MAPK and Chk1. [2]

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.

---

1. After intraperitoneal or oral administration, Rimonabant HCl (SR141716) antagonizes the classical pharmacological and behavioural effects induced by cannabinoid receptor agonists in animals. [1]

2. In the azoxymethane-induced mouse model of colon carcinogenesis, Rimonabant HCl (SR141716) significantly reduces the formation of aberrant crypt foci (ACF), which are precancerous lesions preceding colorectal cancer. [2]

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.

---

1. For evaluating adenylyl cyclase activity: Rat brain membranes are prepared, and the inhibitory effect of cannabinoid receptor agonists on adenylyl cyclase activity is measured. Rimonabant HCl (SR141716) is added to the reaction system, and its ability to antagonize the agonist-induced inhibition of adenylyl cyclase activity is assessed. [1]

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.

---

1. For studying adenylyl cyclase activity in brain membranes: Rat brain membrane preparations are used to detect adenylyl cyclase activity under the influence of cannabinoid receptor agonists, and the antagonistic effect of Rimonabant HCl (SR141716) on the agonist-mediated inhibition is evaluated. [1]

2. For mouse vas deferens contraction studies: Isolated mouse vas deferens tissues are prepared, and the inhibitory effect of cannabinoid receptor agonists on tissue contractions is observed. Rimonabant HCl (SR141716) is administered to determine its ability to reverse the agonist-induced inhibitory effect on contractions. [1]

3. For colorectal cancer cell studies: Human colorectal cancer cell lines (DLD-1, CaCo-2, SW620) are cultured in appropriate medium and treated with Rimonabant HCl (SR141716). After treatment, markers of cell proliferation and cell viability are analyzed, and cell cycle progression is evaluated to observe changes in cell cycle distribution. For DLD-1 cells, mitotic index is measured, and the presence of DNA double-strand breaks and chromosome misjoining events is detected to confirm mitotic catastrophe. Additionally, western blot analysis is performed to examine the expression levels of Cyclin B1, PARP-1, Aurora B, phosphorylated p38/MAPK, and Chk1. [2]

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 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]

---

---

1. Pharmacological and behavioural antagonism studies: Mice and rats are used as experimental animals. Rimonabant HCl (SR141716) is administered via intraperitoneal injection or oral gavage. Subsequently, cannabinoid receptor agonists are administered, and the classical pharmacological and behavioural responses induced by the agonists are observed to evaluate the antagonistic effect of the drug. Specific details such as drug dissolution formulation and administration frequency are not provided. [1]

2. Colon carcinogenesis model studies: Female inbred C57BL mice are used to establish the azoxymethane-induced colon carcinogenesis model. Rimonabant HCl (SR141716) is administered (specific route, frequency, and dissolution formulation not provided) during the model establishment process. After the experimental period, the colon tissues of the mice are collected, and the number of aberrant crypt foci (ACF) is counted to assess the drug's inhibitory effect on precancerous lesion formation. [2]

Absorption, Distribution and Excretion
Undetermined Metabolism/Metabolite Hepatic metabolism, involving CYP3A4. Biological Half-Life 6 to 9 days for normal body mass index (BMI), 16 days for BMI 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 carbazide compound formed by the condensation of the carboxyl 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 type 1 cannabinoid receptor (CB1R) antagonist. In addition to its antagonistic effect, numerous studies have shown that rimonabant can act as a reverse agonist of the CB1 receptor at micromolar concentrations. It was the first selective CB1 receptor antagonist/reverse agonist used clinically to treat obesity and metabolic-related diseases. However, it was later withdrawn from the market due to central nervous system-related adverse reactions, including depression and suicidal ideation. It has dual effects of anti-obesity, CB1 receptor antagonism, and appetite suppression. It belongs to the pyrazole, dichlorobenzene, carbazide, aminopiperidine, and monochlorobenzene classes of compounds. Rimonabant is an anti-obesity and anorexic drug manufactured and marketed by Sanofi-Aventis. It is an inverse agonist of the cannabinoid receptor CB1. Its main mechanism of action is appetite suppression. Rimonaban is the world's first approved selective CB1 receptor blocker. Rimonaban has been approved in 38 countries, including the EU, Mexico, and Brazil. However, its marketing application in the United States was rejected. Previously, a US advisory group recommended against approving the drug because it may increase the risk of suicidal tendencies and depression. It is 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 to treat obesity. Drug Indications: Suitable for patients with a body mass index (BMI) greater than 30 kg/m², or a BMI greater than 27 kg/m² with associated risk factors (such as type 2 diabetes or dyslipidemia), in conjunction with diet and exercise therapy.
As an adjunct to diet and exercise therapy, it is used to treat obese patients (BMI ≥ 30 kg/m²) or overweight patients (BMI ≥ 27 kg/m²) with relevant risk factors (e.g., type 2 diabetes or dyslipidemia) (see Section 5.1).
As an adjunct to diet and exercise therapy, it is used to treat obese patients (BMI ≥ 30 kg/m²) or overweight patients (BMI ≥ 27 kg/m²) with relevant risk factors (e.g., type 2 diabetes or dyslipidemia) (see Section 5.1).

---

Mechanism of Action Rimonaban is a specific CB1 cannabinoid receptor antagonist. Extensive evidence suggests that the endocannabinoid system plays a crucial role in appetite drive and related behaviors. Therefore, it is reasonable to assume that weakening the activity of this system may have therapeutic benefits for treating diseases that may involve overeating or an overactive endocannabinoid system, such as obesity, alcohol and other drug abuse, and various central nervous system and other diseases.

---

Pharmacodynamics
In the RIO-North America trial, 3040 patients were randomized to receive either placebo or two doses of rimonaban (5 mg or 20 mg daily). Compared with the placebo group, patients taking 20 mg of rimonaban showed significant weight loss, waist circumference reduction, improved insulin sensitivity, and elevated high-density lipoprotein cholesterol levels.

---

1. Rimonaban hydrochloride (SR141716) is the first selectively orally effective endocannabinoid (CB1) receptor antagonist. [1]
2. This compound is a powerful tool for studying the function of the endocannabinoid/arachidonic acid ethanolamine (anandamide) system in vivo. [1]
3. Rimonaban hydrochloride (SR141716) has antitumor effects on colorectal cancer cells, as well as on thyroid tumors and breast cancer cells. [2]
4. The antitumor effects of rimonaban hydrochloride (SR141716) in colorectal cancer involve inhibiting cell growth at different stages of colon cancer pathogenesis and inducing mitotic catastrophe in vitro. [2]

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.

---

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.

---

View More

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

---

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