Mini-Reviews in Medicinal Chemistry, 2007, 7, 21-30 21 1389-5575/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Cannabinoid Receptor Antagonists and the Metabolic Syndrome: Novel Promising Therapeutical Approaches C. Cervino, R. Pasquali and U. Pagotto * Endocrinology Unit, Department of Internal Medicine and Gastroenterology and C.R.B.A., S.Orsola-Malpighi Hospital, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy Abstract: Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will pro- vide a concise and updated revision of the state of art on this topic. Key Words: Endocannabinoid, cannabinoid type 1 receptor, cannabinoid type 1 receptor antagonist, rimonabant, metabolic syndrome. INTRODUCTION Obesity has increased at a striking rate over the last three decades in the Western countries. This negative trend dra- matically impacts on physical health and on the relative car- diovascular risk. In fact, particularly when judged at visceral level, obesity is strongly associated with an increased risk of life-threatening conditions such as diabetes, arterial hyper- tension, dyslipidemia and cardiovascular diseases [1]. Waist circumference, both in women and men, provides a conven- ient measure of visceral obesity. Therefore, waist circumfer- ence reduction should be the target of clinical intervention in obese patients [2]. Although lifestyle adjustments, such as nutritional changes and physical activity, are commonly thought of as the milestones of the treatment of obesity, it is now evident that it is necessary to support obese patients with a pharmacological approach for almost two reasons: to further reduce the metabolic risk profile and to avoid regain- ing lost weight. Among the various pharmacological targets explored in recent years, the endocannabinoid system nowadays consti- tutes the most promising and the most intriguing one pro- posed so far. 1. THE ENDOCANNABINOID SYSTEM Cannabinoid research received an important boost by the identification of the chemical structure of 9 -tetrahydrocan- nabinol (THC) (Fig. (1)), the best characterized cannabinoid component of Cannabis Sativa, among several other can- nabinoids present in the plant [3]. The second remarkable success in this field of research was provided by the discov- ery of the CB1 receptor, the binding site of exogenous can- nabinoids and of the synthetic analogs synthesized thereafter [4]. Together with the characterization of another cannabi- noid receptor named CB2 receptor, anandamide (N-arachi- *Address correspondence to this author at the Endocrinology Unit and C.R.B.A, Dept. of Internal Medicine and Gastroenterology, S. Orsola- Malpighi Hospital, Via Massarenti, 9, 40138 Bologna, Italy; Tel: +39-051- 6363009; Fax: +39-051-636080; E-mail: pagube@med.unibo.it donoylethanolamine) (AEA) [5] and 2-arachidonoylglycerol (2-AG) [6, 7], the first endogenous ligands for CB1 and CB2 receptors, derivatives of arachidonic acid, were identified (Fig. (1)). Over the last few years, several other derivatives of long-chain polyunsaturated fatty acids have been de- scribed [8-10]; they appear to act, at least in part, through CB1 and CB2 receptors. Their functions are, however, less characterized when compared to AEA and 2-AG. Although the CB1 receptor was originally described as the “brain type”, because it is the most abundant G protein- coupled receptor in the central nervous system of mammali- ans [11], recent studies highlighted its presence in various peripheral organs including those involved in the control of metabolism such as adipocytes [12-14], hepatocytes [15], endocrine pancreatic cells [16] and skeletal muscle cells [17]. On the other hand, the CB2 receptor is mainly ex- pressed in immune cells and does not seem to play a role in the regulation of metabolic processes, so far [11]. However, as was the case with CB1 receptors, recent evidence has demonstrated that the CB2 receptor is not only limited to immune and hematopoietic cells, but is also present in the brain [18], in the liver [19], in the bone [20] and in the pan- creas [16]. Endocannabinoids are lipophilic substances and their synthesis derives from phospholipid precursors. Unlike other neurotransmitters or hormones, they are not stored in vesi- cles but released “on demand”. This peculiar characteristic needs, therefore, a strict regulation of the different phases of their release, uptake and degradation. In general, the synthe- sis of endocannabinoids is triggered by elevated intracellular concentrations of Ca 2+ , such as during membrane depolariza- tion [see review in 21]. However, Ca 2+ -independent proc- esses have also been proposed to induce endocannabinoid synthesis [22]. Very interestingly, it has recently been shown that non-genomic actions of glucocorticoids can also stimu- late the synthesis of endocannabinoids [23]. Briefly, the formation of AEA occurs in two steps (see review in [21]). Initially, the precursor phosphatidyl ethano- lamine, an abundant lipid present in the cell membrane, ex- changes the ethanolamine moiety with an arachidonic acid