|Biological Activity of Rimonabant:
Rimonabant, also known as SR141716, was the first selective central cannabinoid (CB1) receptor inverse agonist (Ki = 1.8 nM) to be developed as an appetite suppressant, anti-obesity drug. Rimonabant is widely used as a tool to investigate CB receptor properties and the mechanisms by which CB agonists exert their pharmacological effects. In rodent models and clinical trials, rimonabant effectively induces lipolysis, reduces hepatomegaly, decreases body weight, and improves dyslipidemia by reducing triglyceride, free fatty acid, and total cholesterol levels and by increasing HDL/LDL ratios.
|References on Rimonabant:
1 . Mandhane S, Nayak P, Soni D, Jain S, Ashton JC, Rajamannar T. Induction of glucose intolerance by acute administration of rimonabant. Pharmacology. 2012;89(5-6):339-47.
BACKGROUND/AIMS: Rimonabant is a cannabinoid CB1 receptor antagonist. Other CB1 antagonists have biphasic effects on blood glucose levels following acute administration. We therefore tested the effects of rimonabant on glucose tolerance following acute administration.METHODS: We tested the effects of oral and intracerebroventricular administration of rimonabant on blood glucose and gastrointestinal transit in mice following oral and intravenous glucose challenge.RESULTS: We found a dose-dependent increase in blood glucose from oral doses of rimonabant of 3 mg/kg and above. WIN55,212-2 (3 mg/kg), a cannabinoid receptor agonist, did not influence blood glucose in the presence or absence of rimonabant. Rimonabant did not induce release of glucose from isolated rat hepatocytes or modify serum insulin concentration in mice. Intracerebroventricular administration of rimonabant caused increases in blood glucose and gastrointestinal transit, suggesting a central nervous system site of action. Increases in blood glucose by rimonabant were partially blocked by the dopamine receptor antagonist haloperidol and significantly blocked by the 5-hydroxytryptophan(5-HT) depleting agent p-CPA and the 5-HT 3 receptor antagonist ondansetron.CONCLUSIONS: Rimonabant causes dose-dependent increase in glucose profile upon glucose challenge partially mediated by the central nervous system control of gastrointestinal carbohydrate absorption through pathways that are modulated by both 5-HT and dopamine.
2 . Seely KA, Brents LK, Franks LN, Rajasekaran M, Zimmerman SM, Fantegrossi WE, Prather PL. AM-251 and rimonabant act as direct antagonists at mu-opioid receptors: Implications for opioid/cannabinoid interaction studies. Neuropharmacology. 2012 Oct;63(5):905-15.
Mu-opioid and CB1-cannabinoid agonists produce analgesia; however, adverse effects limit use of drugs in both classes. Additive or synergistic effects resulting from concurrent administration of low doses of mu- and CB1-agonists may produce analgesia with fewer side effects. Synergism potentially results from interaction between mu-opioid receptors (MORs) and CB1 receptors (CB1Rs). AM-251 and rimonabant are CB1R antagonist/inverse agonists employed to validate opioid-cannabinoid interactions, presumed to act selectively at CB1Rs. Therefore, the potential for direct action of these antagonists at MORs is rarely considered. This study determined if AM-251 and/or rimonabant directly bind and modulate the function of MORs. Surprisingly, AM-251 and rimonabant, but not a third CB1R inverse agonist AM-281, bind with mid-nanomolar affinity to human MORs with a rank order of affinity (K(i)) of AM-251 (251 nM) > rimonabant (652 nM) > AM281 (2135 nM). AM-251 and rimonabant, but not AM-281, also competitively antagonize morphine induced G-protein activation in CHO-hMOR cell homogenates (K(b) = 719 or 1310 nM, respectively). AM-251 and rimonabant block morphine inhibition of cAMP production, while only AM-251 elicits cAMP rebound in CHO-hMOR cells chronically exposed to morphine. AM-251 and rimonabant (10 mg/kg) attenuate morphine analgesia, whereas the same dose of AM-281 produces little effect. Therefore, in addition to high CB1R affinity, AM-251 and rimonabant bind to MORs with mid-nanomolar affinity and at higher doses may affect morphine analgesia via direct antagonism at MORs. Such CB1-independent of these antagonists effects may contribute to reported inconsistencies when CB1/MOR interactions are examined via pharmacological methods in CB1-knockout versus wild-type mice.
3 . Heppenstall C, Bunce S, Smith JC. Relationships between glucose, energy intake and dietary composition in obese adults with type 2 diabetes receiving the cannabinoid 1 (CB1) receptor antagonist, rimonabant. Nutr J. 2012 Jul 23;11(1):50.
BACKGROUND: Weight loss is often difficult to achieve in individuals with type 2 diabetes and anti-obesity drugs are often advocated to support dietary intervention. Despite the extensive use of centrally acting anti-obesity drugs, there is little evidence of how they affect dietary composition. We investigated changes in energy intake and dietary composition of macro- and micronutrients following therapy with the endocannabinoid receptor blocker, rimonabant.METHODS: 20 obese patients with type 2 diabetes were studied before and after 6 months dietary intervention with rimonabant. Dietary intervention was supervised by a diabetes dietician. Five-day food diaries were completed at baseline and at 6 months and dietary analysis was performed using computer software (Dietplan 6).RESULTS: After 6 months, (compared with baseline) there were reductions in weight (107+/-21Kg versus 112+/-21, p<0.001, 4% body weight reduction), and improvements in HbA1c (7.4+/-1.7 versus 8.0+/-1.6%, p<0.05) and HDL cholesterol. Intake of energy (1589+/-384 versus 2225+/-1109kcal, p<0.01), carbohydrate (199+/-74 versus 273+/-194g, p<0.05), protein (78+/-23 versus 98+/-36g, p<0.05), fats (55+/-18 versus 84+/-39g, p<0.01) and several micronutrients were reduced. However, relative macronutrient composition of the diet was unchanged. Improvement in blood glucose was strongly correlated with a reduction in carbohydrate intake (r = 0.76, p<0.001).CONCLUSIONS: In obese patients with type 2 diabetes, rimonabant in combination with dietary intervention led to reduced intake of energy and most macronutrients. Despite this, macronutrient composition of the diet was unaltered. These dietary changes (especially carbohydrate restriction) were associated with weight loss and favourable metabolic effects.
4 . Erdozain, A. M. et al. The inverse agonist effect of rimonabant on G protein activation is not mediated by the cannabinoid CB1 receptor: Evidence from postmortem human brain Biochemical Pharmacology (2012), 83(2), 260-268.
5 . Leite, C.E., Mocelin, C.A., Petersen, G.O., et al. Rimonabant: An antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep 61 217-224 (2009).
Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. ...