Elsevier

Vitamins & Hormones

Volume 81, 2009, Pages 159-189
Vitamins & Hormones

Chapter 7 Cannabinoid Receptor CB1 Antagonists: State of the Art and Challenges

https://doi.org/10.1016/S0083-6729(09)81007-8Get rights and content

Abstract

The discovery of cannabinoid receptors led to the development of several compounds targeted against these receptors. In particular, CB1 receptor antagonists have been described to possess key functions in the treatment of obesity and obesity‐related pathologies. Numerous clinical trials revealed the advantage of strategies designed to block CB1 receptor but also evidenced the limitations due to side effects exerted by these substances. Recent studies have highlighted that CB1 antagonists could have other effects and find applications even in other pathologies like hepatic fibrosis, chronic inflammatory conditions, diabetes, and cancer. Since the suspending sales of the lead compound, rimonabant, and the discontinuation of all ongoing clinical trials of CB1 blockers, alternative strategies could emerge and lead to the development of further basic research studies to redirect these compounds.

Introduction

Cannabinoids are the main constituents of the marijuana plant (Cannabis sativa), and it is well known that Δ‐9‐tetrahydrocannabinol (THC) is the primary psychoactive substance in marijuana. Two receptor sites for cannabinoids have been cloned: the most abundant CB1 and the more restricted CB2. Since CB receptors discovery, two major endogenous cannabinoids (endocannabinoids) have been identified: anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) (Devane et al., 1992, Matsuda et al., 1990, Munro et al., 1993). Both eicosanoids are derived from lipids and chemically characterized by an arachidonoic acid moiety. A set of enzymes catalyze their biogenesis and degradation (Blankman et al., 2007, Liu et al., 2008, Wang and Ueda, 2008) and together with CB receptors and their endogenous ligands comprise the endocannabinoid system (EC).

Numerous evidences showed that the EC system plays a significant role not only in appetite drive and associated behaviors, but also in endocrine and metabolic regulation and energy balance (Pagotto et al., 2006). Indeed, CB receptors, especially CB1 receptors, are present not only in the brain, but also in peripheral organs, that is, adipose tissue, gut, liver, skeletal muscle, and pancreas (Cota, 2007; Matias and Di Marzo, 2007, Pagotto et al., 2006). They participate in the physiological modulation of many central and peripheral functions (Cota, 2007, Matias and Di Marzo, 2007, Pagotto et al., 2006). Many studies 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. In particular, EC system overactivity has been demonstrated in human obesity, especially in the visceral adipose tissue (Cote et al., 2007, Deedwania, 2009, Matias et al., 2006), which is closely related to high risk of type 2 diabetes and cardiovascular diseases (CVD) (Després and Lemieux, 2006, Van Gaal et al., 2006). The presence of the EC system and CB1 receptors in several organs that play an important role in metabolic disturbances offers a great opportunity for new pharmacological approaches (Di Marzo et al., 2004, Pacher et al., 2006). With the growing worldwide epidemic of both obesity and diabetes mellitus, efforts have intensified to find novel therapies to help patients to lose weight and either to prevent or to control diabetes and its associated cardiovascular diseases. Weight loss is associated with favorable changes in lipid profiles and C‐reactive protein, as well as with improved glycemic control and decreased mortality. However, success with behavior modification and currently available medications in achieving and sustaining even mild weight loss is limited. Thus, the EC system represents a new target for pharmacological modulation (Di Marzo et al., 2004, Pacher et al., 2006) and its manipulation via blockade of the CB1 receptor is intriguing particularly in the treatment of obesity and related pathologies.

The aim of this chapter is to evidence the recent emerging knowledge about the modulation of CB1 receptors by their antagonists highlighting the promising therapeutic potential applications and the related difficulties of these compounds.

Section snippets

Endocannabinoid System: Control of Energy Balance

Based on the abundance of CB1 receptors in the brain and the tightly regulated expression of endocannabinoids in tegmental area where modulation of rewarding properties of food occurs, and in the hypothalamus where food intake is centrally regulated (Herkenham et al., 1990, Melis et al., 2004), the EC system is considered a major homeostatic system controlling energy balance.

In the central nervous system (CNS) endocannabinoids are synthesized by neurons in response to depolarization (Freund et

Cannabinoid CB1 Receptors and CB1 Antagonists

The CB1 receptor is expressed in the cortex, striatum, hippocampus, and cerebellum (Howlett, 2005), found predominantly at central and peripheral nerve terminals, mediates inhibition of transmitter release (Howlett et al., 2002). It is also expressed at lower levels by certain non‐neuronal cells and tissues, for example the pituitary gland, immune cells, and reproductive tissues. The CB1 receptor belongs to the G protein‐coupled receptor (GPCR) type and is coupled to G proteins and inhibits

Clinical trials

The interest to develop cannabinoid antagonists derives from the multiple functions in which the endogenous cannabinoid system is involved mainly the control of appetite and lipid and glucose metabolism (for a review, see Di Marzo, 2008a, Piomelli et al., 2000). We will focus more in detail on the effects of rimonabant as this lead compound has been widely used and described in literature (for a review, see Bifulco et al., 2007a). The pharmacokinetic/pharmacodynamic profile of rimonabant, as

Other Emerging Effects of CB1 Antagonists

Many studies conducted with rimonabant showed its pleiotropic effects from obesity to drug dependence and memory impairment (Bifulco et al., 2007a). In this section, we aim to mention recent findings on antitumor properties of rimonabant (and other antagonists) as these studies suggest that targeting the EC system, via modulation of the CB1 receptor, could be a promising therapeutic strategy for cancer management.

The studies conducted from the late 1990s on the endocannabinoid system have

Therapeutic Prospects

The CB1 receptors have been considered for years main targets in the treatment of obesity and obesity‐related pathologies. Although the CB1 antagonists have been widely used in clinical trials, it is recent news that the European Medicines Agency recommended suspending sales of the lead compound, rimonabant, which has been approved in Europe for 2 years but has not been approved in the US. The reason provided by the agency is that the experience with rimonabant since approval has indicated that

Conclusions

In light of the public health implications of the obesity pandemic, CB1 blockade strategy aimed to treat obesity and related disorders has encouraged several pharmaceutical companies in these years to develop new and more selective CB1 antagonists.

The literature currently available on the effects of CB1 antagonists, particularly rimonabant, demonstrates that the use of these drugs is controversial due to the double aspect concerning their potential as antiobesity molecules and their side

Acknowledgments

We thank the Associazione Educazione e Ricerca Medica Salernitana (ERMES) for supporting our studies. A.M. Malfitano was supported by a fellowship from AIRC.

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