Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Abstract

The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large-scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.Studies on the effect of marijuana psychoactive principle ⌬ 9 -tetrahydrocannabinol (THC) have evolved into the discovery and description of the endocannabinoid system. So far, this system is composed of two receptors (the widely expressed CB1 and the more restricted CB2), five endogenous lipid-like ligands [including the well known endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol], and the enzymes involved in their biosynthesis and degradation (for review, see Mechoulam et al., 1998;De Petrocellis et al., 2004;Di Marzo et al., 2004). Starting from the discovery of the endocannabinoid system, a number of studies have pointed out that altered endocannabinoid signaling and CB1 receptor expression are involved in several pathophysiological situations, ranging from neurological and psychiatric diseases to eating, cardiovascular, and reproductive disorders. More recently, it has been described that CB1 receptor stimulation by the endocannabinoid AEA can negatively modulate cancer cell proliferation in vitro (Bifulco et al., 2001 as well as tumor growth and metastatic spreading in vivo (Portella et al., 2003;Bifulco et al., 2006Bifulco et al., , 2007. CB1 or CB2 antagonistic or inverse agonistic compounds have been used to investigate the endocannabinoid network and its integration with other signaling transduction pathways (for review, see Lange and Kruse, 2005). The first highly selective CB1 receptor antagonist, rimonabant (SR141716; Acomplia) was discovered by Sanofi-Aventis (Bridgewater, NJ) (Rinaldi-Carmona et al., 1994). It showed a number of biological effects in vitro and in vivo in several pathological situations. An update on the pleiotropic effects of rimonabant does not exist, whereas the knowledge concerning endocannabinoid system has been expanded considerably; therefore, we critically analyze the current literature on the pharmacological potential of rimonabant. We aim to describe both We thank the Associazione Educazione e Ricerca Medica Salernitana (ERMES) for supporting our studies. A.S. was supported by a fellowship from Associazione Italiana Ricerca sul Cancro.Article, publication date, and citation information can be found at

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…43 However, it may also offer other potential therapeutic opportunities which are currently under investigation or will be considered sooner or later in clinical trials. 18, 47 The most impressive data arose from the RIO programme in overweight/obese individuals with or without comorbidities. 19,23,43 In this clinical research programme, two doses of rimonabant (5 mg and 20 mg) were compared to placebo, but only the dose of 20 mg has been commercialized (see below).…”

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

“…Thus rimonabant (and related compounds) offers a possible approach to prevention or treatment of the metabolic syndrome, prediabetic status, and associated micro-and macrovascular sequelae (3). More recently, the role of the CB 1 receptor in intestinal physiology, intestinal inflammation, and conditions of obesity has become apparent (21,22).…”

Anandamide Biosynthesis Catalyzed by the Phosphodiesterase GDE1 and Detection of Glycerophospho-N-acyl Ethanolamine Precursors in Mouse Brain

“…Validation of this route for AEA biosynthesis through, for example, the creation of mice lacking Abh4 or GDE1, would designate these enzymes as principal regulators of endocannabinoid signaling in vivo and potential therapeutic targets for a range of human disorders, including obesity, smoking cessation, and cancer (28). …”