Biological Activity
| Description |
Rimonabant is a selective antagonist of CB1 with IC50 of 13.6 nM and EC50 of 17.3 nM in hCB1 transfected HEK 293 membrane. |
| Targets |
hCB1 |
hCB2 |
Acuyl coenzyme A:cholesterol acyltransferase (ACAT |
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| IC50 |
13.6 nM |
1.64 μM [1] |
1.5-2.9 μM [2] |
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| In vitro |
Rimonabant dose-dependently reduces ACAT activity in Raw264.7macrophages with IC50 of 2.9 μM and isolated peritoneal macrophages. Rimonabant inhibits ACATactivity in intact CHO-ACAT1 and CHO-ACAT2 cells and in cell-free assays with approximately equal efficiency with IC50 of 1.5 μM and 2.2 μM for CHO-ACAT1 and CHO-ACAT2, respectively. Consistent with ACAT inhibition, Rimonabant treatment blocks ACAT dependent processes in macrophages, oxysterol-induced apoptosis and acetylated-LDL induced foam cell formation. [2] Rimonabant antagonizes the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes in a concentration-dependent manner. [3] Rimonabant significantly reduces cell growth and induces cell death of human colorectal cancer cells (DLD-1, CaCo-2 and SW620). Rimonabant is able to alter cell cycle distribution in all the cell lines tested. Particularly, Rimonabant produces a G2/M cell cycle arrest in DLD-1 cells without inducing apoptosis or necrosis. [4] |
| In vivo |
Rimonabant is administered intraperitoneally or orally potently and dose-dependently antagonize classical pharmacological and behavioural effectos of cannabinoid receptor agonists. [3] In the mouse model of azoxymethane-induced colon carcinogenesis, Rimonabant significantly decreased aberrant crypt foci (ACF) formation, which precedes colorectal cancer. [4] Rimonabant (10 mg/kg by gavage) is fed for 2 weeks to 3-month-old male obese Zucker rats as an impaired glucose tolerance model and for 10 weeks to 6-month-old male obese Zucker rats as a model of the metabolic syndrome. RANTES (Regulated upon Activation, Normal T cell Expressed, and Secreted) and MCP-1 (monocyte chemotactic protein-1) serum levels are increased in obese vs lean Zucker rats and significantly reduced by long-term treatment with Rimonabant, which slowes weight gain in rats with the metabolic syndrome. Neutrophils and monocytes are significantly increased in young and old obese vs lean Zucker rats and lowered by Rimonabant. Platelet-bound fibrinogen is significantly enhanced in obese vs lean Zucker rats of both age, and is reduced by Rimonabant. Platelets from obese rats are more sensitive to thrombin-induced aggregation and adhesion to fibrinogen, which are both attenuated by Rimonabant therapy. [5] |
| Clinical Trials |
Rimonabant is now under the Phase III clinical trial for the effects on weight gain and body composition in adults with Prader Willi Syndrome. |
| Features |
Rimonabant has been used to afford weight reduction and improvements in cardiometabolic risk factors, however is withdrawn in 2009 due to the severe depressive disorder and anxiety. |
Protocol(Only for Reference)
Kinase Assay: [1]
| Radioligand Binding Assay |
Human CB1 and CB2 stably transfect HEK 293 cells and cell membrane is purified. 0.2-8 μg of the purified membrane is incubated with 0.75 nM [3H] CP55,940 and Rimonabant in the incubation buffer (50 mM Tris-HCl, 5 mM MgCl2, 1 mM EDTA, 0.3%BSA, pH 7.4). The non-specific binding is defined in the presence of 1 μM of CP55,940. The reactions are incubated for one and a half hours at 30 °C in Multiscreen. The reactions are terminated by manifold filtration and washed four times with ice-cold wash buffer (50mM Tris, pH 7.4, 0.25% BSA).The radioactivity bound to the filters is measured by Topcount. The IC50 is determined as the concentration of Rimonabant required to inhibit 50% of the binding of [3H] CP55,940 and calculated by non-linear regression. |
| Eu-GTP Binding Assay |
The Eu-GTP binding assay is performed using the DELFIA Eu-GTP binding kit based on methods developed by Frang et al., with minor modifications as described in the following: 1-4 μg of purified membrane is incubated with Rimonabant and 20 nM CP55,940 in the assay buffer (50 mM HEPES, pH 7.4, 100 mM NaCl, 100 μg/mL saponin, 5 mMMgCl2, 2 μM GDP, 0.5% BSA) at 30 °C for 60 minutes in acroplates. Following the addition of Eu-GTP and incubation for 30 minutes at 30 °C, the assay is terminated by washing four times with the washing buffer provided in the kit. The fluorescence signal of the Eu-GTP is determined with a Victor 2 multilabel reader. The EC50 of Rimonabant at inhibiting 50% of the CP55,940-stimulated Eu-GTP binding is determined from the dose-response curves using non-linear regression. [2] |
Cell Assay: [2]
| Cell lines |
Raw 264.7 cells |
| Concentrations |
0,1,4 μM |
| Incubation Time |
17 hours |
| Method |
Raw 264.7 cells (2 × 106 /well) in 12-well plates are rinsed with PBS and refed culture media supplemented with varying amounts of Rimonabant 1 hour prior to supplementation with 7-ketocholesterol (7KC). All wells are adjusted to receive equal amounts of vehicle. Following 16-hour incubation, caspase-3 and caspase 3-like activity are determined using a fluorogenic substrate (Ac-DEVD-AFC) and a spectrofluorometer equipped with a microplate reader. |
Animal Study: [3]
| Animal Models |
Male mice and male rats |
| Formulation |
Rimonabant is dissolved in two drops of Tween 80, diluted in distilled water. |
| Dosages |
20 ml/kg (mice) and 5 ml/kg (rats) |
| Administration |
Rimonabant is administered i.p. (30 minutes) or p.o. (1hour) before the i.v. injection of WIN55212-2. |
1
References
[1] Chu CM, et al, Org Biomol Chem, 2008, 6(18), 3399-3407
[2] Netherland C, et al, Biochem Biophys Res Commun, 2010, 398(4), 671-676.
[3] Rinaldi-Carmona M, et al, FEBS Lett, 1994, 350(2-3), 240-244.
[4] Santoro A, et al, Int J Cancer, 2009, 125(5), 996-1003.
[5] Schafer A, et al, Br J Pharmacol, 2008, 154(5), 1047-1054.
[6] Wise LE, et al, Neuropsychopharmacology, 2007, 32(8), 1805-1812.
Download Rimonabant (SR141716) SDF
| Molecular Weight (MW) |
463.79 |
| Formula |
C22H21Cl3N4O
|
| CAS No. |
168273-06-1 |
| Synonyms |
N/A |
Solubility (25°C)
- DMSO 25 mg/mL
- Water <1 mg/mL
- Ethanol 2 mg/mL
|
| Storage |
2 years -20°CPowder |
| 2 weeks4°Cin DMSO |
| 6 months-80°Cin DMSO |
| Chemical Name |
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide |
Research Area
Tech Support & FAQs
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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