Rimonabant: New data and emerging experience

Abstract

The endogenous cannabinoid system has been identified as playing a central role in the regulation of energy homeostasis, and its overactivity has been associated with obesity. Rimonabant is a selective endocannabinoid CB(1) receptor antagonist that has been shown to be an effective treatment for obesity and cardiometabolic risk factors. Studies comparing 20 mg/d of rimonabant with placebo show a placebo-subtracted weight loss between 6.3 and 6.9 kg at 1 year. In addition to the health benefits already associated with weight loss, rimonabant has shown additional improvements in lipid and glycemic cardiometabolic biomarkers such as low-density lipoprotein cholesterol, triglycerides, C-reactive protein, glucose, and adiponectin. The use of endocannabinoid antagonists such as rimonabant provides a promising therapeutic approach to the treatment of obesity and its associated cardiometabolic risks.

Regulation of MAP Kinase–Directed Mitogenic and Protein Kinase B–Mediated Signaling by Cannabinoid Receptor Type 1 in Skeletal Muscle Cells

“…SR141716 (rimonabant) is a selective CB1 receptor inverse agonist (trade name Acomplia) that has been used to treat obesity (35). Administration of SR141716 causes a transient reduction in food intake and sustained reduction in body weight gain as well as decreases hyperinsulinemia and reduces circulating levels of free fatty acids in diet-induced obese rodents and in humans (17,22).…”

The endocannabinoid system in obesity and type 2 diabetes

“…AEA, anandamide; HFD, high-fat diet Potential consequences Site of action sequences, and in hepatosteatosis, comes from studies carried out in animal models of these two metabolic disorders involving congenital or prolonged pharmacological blockade of CB 1 receptors, as well as from the five published clinical studies on the chronic administration of CB 1 receptor antagonists/inverse agonists. These studies were recently reviewed (for examples, see [63][64][65]) and will only be briefly discussed here.…”

“…The data have been subject to different interpretations [78,80], but clearly point to depressive disorders, nausea, anxiety and dizziness as the most frequent side effects leading to discontinuation. Importantly, antecedents of depression increase the risk of recurrent depressive disorders during subsequent rimonabant therapy, and severe depression and concomitant antidepressant treatment are contraindications to rimonabant prescription [65,78]. This needs to be taken into account when prescribing CB 1 The treatment group received an oral dosage of 20 mg/day for 1 year a Occurring in ≥2% of the rimonabant (20 mg) group and in ≥1% of the placebo group b Incidence increased by >0.5% between placebo group and rimonabant (20 mg/day) group Based on data from [78] antagonists to patients with obesity and type 2 diabetes, particularly since depression and anxiety are often described as accompanying these disorders, and weight loss per se can induce mood disturbances [65].…”

“…Importantly, antecedents of depression increase the risk of recurrent depressive disorders during subsequent rimonabant therapy, and severe depression and concomitant antidepressant treatment are contraindications to rimonabant prescription [65,78]. This needs to be taken into account when prescribing CB 1 The treatment group received an oral dosage of 20 mg/day for 1 year a Occurring in ≥2% of the rimonabant (20 mg) group and in ≥1% of the placebo group b Incidence increased by >0.5% between placebo group and rimonabant (20 mg/day) group Based on data from [78] antagonists to patients with obesity and type 2 diabetes, particularly since depression and anxiety are often described as accompanying these disorders, and weight loss per se can induce mood disturbances [65]. A similar, albeit not completely overlapping, safety profile emerges from the Phase II trial on taranabant [75], although in this case the smaller number of patients participating in the study did not allow any definitive conclusion to be drawn.…”

Solid-state NMR and molecular dynamics characterization of cannabinoid receptor-1 (CB1) helix 7 conformational plasticity in model membranes

“…Hyperactive CB1-receptor transmission has been implicated in many common diseases having a reward-supported component, such as overweight/obesity and substance abuse disorders [15]. Indeed, the first major drug to emerge from rational discovery efforts aimed at endocannabinoid-system modulation reached the market as a CB1-receptor antagonist for weight-control [16]. The CB1 receptor, accordingly, has gained intense current interest in medicinal chemistry as a therapeutic target for designer ligands and as the focus of research aimed at defining its ligand-binding architecture for therapeutic gain [15,17].…”