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.

Endocannabinoid-Mediated Control of Synaptic Transmission

“…Several selective CB 1 antagonists are currently in advanced preclinical or clinical trials, and rimonabant (SR141716A) has been approved as a weight-management drug in some markets. Multiple, large, randomized, and placebo-controlled international trials in Europe and North America provide clear evidence that rimonabant facilitates weight loss at a therapeutic dose (91,541).…”

The common pathophysiology underlying the metabolic syndrome, schizophrenia and depression. A review

“…Unfortunately, marketing of the first drug, rimonabant, was discontinued for psychiatric sideeffects, namely inducing depressive states and suicidal ideas 103,104 . However, newer cannabinoid compounds are emerging and a strong influence on appetite, metabolism and energy homeostasis is consistently reported [105][106][107] . Most importantly, preclinical studies are constantly widening the range of new candidate molecules [108][109][110] .…”

(4-(Bis(4-Fluorophenyl)Methyl)Piperazin-1-yl)(Cyclohexyl)Methanone Hydrochloride (LDK1229): A New Cannabinoid CB1 Receptor Inverse Agonist from the Class of Benzhydryl Piperazine Analogs

“…Structurally, the benzhydryl piperazine analogs are distinct from the first generation of CB 1 inverse agonists, which generally possess nitrogen-containing five-or sixmember aromatic rings as their central connecting units (Lange and Kruse, 2005;Vemuri et al, 2008;Chorvat, 2013). In contrast, benzhydryl piperazine analogs have a central core of piperazine, which is nonaromatic and possesses basic amino group(s).…”