Cannabinoid 1 G protein-coupled receptor (periphero-)neutral antagonists: emerging therapeutics for treating obesity-driven metabolic disease and reducing cardiovascular risk

Abstract

Introduction: Obesity and related cardiometabolic derangements are spiraling global health problems urgently in need of safe, effective and durable pharmacotherapy.

Areas covered: As an orexigenic and anabolic biosignaling network, the endocannabinoid system interacts with other information-transducing pathways to help ensure metabolic homeostasis. Hyperphagia stimulates reinforcing neuronal circuits favoring energy intake and conservation, inviting overweight/obesity and cardiometabolic risk factors (‘metabolic syndrome’). Associated increases in cannabinoid 1 G protein-coupled receptor (CB1R) activity/expression further exacerbate food consumption and the metabolic shift toward fat production and accumulation. The role of CB1R activity in hyperphagia and weight gain spurred the development of rimonabant (SR141716; Acomplia), the first-in-class CB1R antagonist/inverse agonist weight-loss drug. Rimonabant and similar CB1R inverse agonists also exert pleiotropic actions in addition to weight-loss effects that help correct obesity-related metabolic derangements and reduce cardiovascular risk in humans. The medicinal utility of these agents was crippled by clinically significant central and peripheral adverse effects that appear to reflect CB1R inverse agonists as a class. Consequently, increased attention is being given to CB1R neutral antagonists, CB1R blockers with intrinsically weak, if any, functional potency to elicit the negative-efficacy responses associated with inverse agonists. Laboratory studies demonstrate that CB1R neutral antagonists – whether readily accessible to the central nervous system or not (i.e., ‘periphero-neutral’ antagonists) – retain the salient therapeutic effects of CB1R inverse agonists on hyperphagia, weight-gain, and obesity-driven metabolic abnormalities with the distinct advantage of being associated with significantly less preclinical adverse events than are conventional CB1R inverse agonists such as rimonabant.

Expert opinion: CB1R (periphero-)neutral antagonists merit continued analysis of their molecular pharmacology and evaluation of their therapeutic significance and translational potential as new-generation medicines for obesity-related derangements, including nonalcoholic fatty liver disease and type 2 diabetes, if not obesity itself.

Keywords:

• cardiovascular risk
• cell signaling
• diabetes
• dyslipidemia
• energy balance
• insulin
• leptin
• metabolic syndrome
• nonalcoholic fatty liver disease
• obesity
• steatosis

Acknowledgements

We thank C Paronis and T Järbe, Northeastern University, for helpful discussions regarding preclinical behavioral paradigms.

This paper is dedicated to M Daniel Lane, Distinguished Service Professor, Johns Hopkins University School of Medicine (Baltimore, Maryland) in recognition of his retirement following over a half-century of biomedical research that advanced our understanding of enzymology, receptor biology, protein structure and function, intermediary metabolism and its regulation, cell differentiation and signal transduction. During his tenure as DeLamar Professor and Director of the Department of Biological (formerly Physiological) Chemistry, Johns Hopkins University School of Medicine, Dr. Lane served as postdoctoral mentor to one of the authors (DRJ) when he was a National Institutes of Health Fellow at the Hopkins Medical Institutions. A supportive, kind, generous mentor and formidable intellectual resource, Dr. Lane helped create and sustain the field of modern biochemistry through his own scientific training, his teaching and research, and his professional associations at Johns Hopkins and elsewhere that included S Ochoa, H Wood, F Lynen, A Lehninger and others who laid the foundations of the discipline [303,304].

Notes

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