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.
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