Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis

Abstract

The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimon-abant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant's market withdrawal in the European Union and suspension of rimonabant's, taranabant's, and otenabant's ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.

Keywords::

• 2-arachidonoylglycerol
• addiction
• AM4113
• anandamide
• clinical trial
• diabetes
• drugs
• endocannabinoid
• G protein-coupled receptor
• immunomodulation
• inflammation
• insulin resistance
• ligands
• metabolic syndrome
• neutral antagonist
• obesity
• overweight
• pain
• rimonabant
• steatosis
• substance abuse
• taranabant
• translational biomedicine

Acknowledgements

This article is dedicated to the memory of two influential educators and scientists in commemoration of their passing in 2008. Billy R Martin PhD was universally recognized as one of the leading pharmacologists in the cannabinoid field through his decades of research at the medical campus of Virginia Commonwealth University. George E Palade MD, Nobel Laureate (Physiology and Medicine), founded the field of modern cell biology and served as a graduate mentor to one of the authors (DRJ) while chairing the Department of Cell Biology at the Yale University School of Medicine.

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