Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome

Abstract

Endogenous signaling lipids ("endocannabinoids") functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.

Fig. 1

Chemical structures of the phytocannabinoids Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol and the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). In this and all other structure figures (i.e., Figs. 3–6), comparative Ki or IC₅₀ values for ligand binding to CB1 and CB2 receptors are given (when available) from literature references cited in the relevant text.

Fig. 2

Diagrammatical representation of central nervous system (CNS) endocannabinoid signaling. In response to a stimulus-induced intracellular calcium increase, the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are synthesized in post-synaptic neurons. AEA synthesis starts with N-acylation of phosphatidylethanolamine (PE) by enzyme-catalyzed transfer of an arachidonic-acid (AA) moiety from a donor membrane phospholipid (such as phosphatidylcholine) to form N-arachidonoyl-phosphatidylethanolamine (NAPE), which may then hydrolyzed by, for example, phospholipase D (PL-D) or acted upon by phospholipase C (PL-C) followed by phosphatase action on the resulting phosphoAEA to yield AEA. 2-AG is synthesized in many tissues by lipolysis of diacylglycerol (DAG). The endocannabinoids are then released from post-synaptic neurons and traverse the synaptic cleft (aided, perhaps, by carrier proteins) to pre-synaptic neurons, where they function as retrograde messengers by binding to cannabinoid receptors: AEA has the greater affinity for the CB1 receptor, whereas 2-AG binds preferentially to the relatively minute population of CB2 receptors in the CNS. The signaling through both receptors is coupled to G-proteins (Ⓖ) to elicit a bioresponse. Pre-synaptic monoacylglycerol (MAG) lipase inactivates 2-AG, and post-synaptic fatty acid amide hydrolase (FAAH) inactivates AEA. Endocannabinoid uptake may be facilitated by transmembrane protein transporters. In this manner, endocannbinoids regulate synaptic transmission of excitatory and inhibitory circuits.

Fig. 3

Chemical structures of synthetic cannabinoid receptor ligands that serve as ethical medications.

Fig. 4

Chemical structures of cannabinoid receptor ligands widely used as experimental agents.

Fig. 5

Chemical structures of candidate CB1 receptor antagonists identified in the literature for their development potential as anti-obesity drugs.

Fig. 6

Chemical structures of CB1 receptor antagonists reported to be in clinical development as anti-obesity pharmacotherapeutics.