Cannabinoid CB1 receptor inverse agonists and neutral antagonists: Effects on food intake, food-reinforced behavior and food aversions

Abstract

Drugs that interfere with cannabinoid CB1 receptor transmission suppress a number of food-related behaviors, and these compounds are currently being assessed for their potential utility as appetite suppressants. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251 and AM1387. Biochemical studies indicate that most of the drugs assessed thus far have been CB1 inverse agonists, and these drugs all act to suppress food intake and disrupt food-reinforced behavior. Behavioral tests involving intake of different diets (i.e., high fat, high carbohydrate, laboratory chow) indicate that consumption of all three food types is disrupted by CB1 inverse agonists, and that, expressed as a percent of baseline intake, the effect is roughly comparable across different diets. Although CB1 inverse agonists do not appear to produce severe motor impairments that disrupt feeding behavior, there is evidence that they can induce nausea and malaise. Recent studies have been undertaken to characterize the behavioral effects of CB1 receptor neutral antagonists such as AM4113 to determine if these drugs can reduce feeding and foodreinforced behaviors. Across a variety of different tests, AM4113 produces effects on food-motivated behavior that are very similar to those produced by CB1 inverse agonists. Moreover, this drug did not induce conditioned gaping in rats or vomiting in ferrets. These results suggest that CB1 receptor neutral antagonists may decrease appetite by blocking endogenous cannabinoid tone, and that these drugs may be less associated with nausea than is the case for CB1 inverse agonists.

Cannabinoid Discrimination and Antagonism by CB1Neutral and Inverse Agonist Antagonists

“…From this perspective, the development of neutral CB 1 antagonists might yield safer, yet still effective therapeutics for appetite suppression and, possibly, smoking cessation. Indeed, recent laboratory data appear to support this suggestion, indicating that AM4113 and other newly developed CB 1 neutral antagonists may not produce rimonabant-like effects of nausea, emesis, and anhedonia in laboratory animals (Chambers et al, 2007;Salamone et al, 2007;Sink et al, 2008;Cluny et al, 2010;Jutkiewicz et al, 2010;Cluny et al, 2011). Importantly, AM4113, like rimonabant, also has been shown to reliably reduce weight gain in laboratory animals, consistent with the idea that its potentially beneficial effects are linked to CB 1 receptor blockade (Chambers et al, 2007;Sink et al, 2008;Cluny et al, 2011).…”

“…However, the peripherally restricted CB 1 neutral antagonist AM6545 has been shown to reduce food intake and body weight without inducing nausea (or gaping) in rats (Cluny et al, 2010). Likewise, the centrally acting CB 1 neutral antagonist AM4113 has been shown to reduce food intake in rats (Cluny et al, 2011) without causing nausea/gaping in rats (Salamone et al, 2007;Sink et al, 2008), vomiting in ferrets (Chambers et al, 2007;Salamone et al, 2007), or prodepressant effects in the rat forced swim test (Jutkiewicz et al, 2010). On the basis of such observations, neutral CB 1 antagonists have been forwarded as a promising avenue of drug development that provide clinical benefits like those of rimonabant but, potentially, without its liability for adverse gastrointestinal and/or mood-altering effects (Meye et al, 2012).…”

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…The ligands can be competitive antagonists of CB1-receptor activation by endogenously released ECs (neutral antagonists), or they can act as inverse agonists modulating constitutive CB1-receptor activity by shifting it from an active 'on' to an inactive 'off' state. 18,38,39 Among the increasing number of substances sharing CB1-receptor-antagonist properties, the diarylpyrazole derivative SR141716 (rimonabant) was the first selective one reported 40,41 and extensively investigated. 42,43 It is also the only one already commercialized in various countries.…”

Regulation of food intake and the development of anti-obesity drugs

“…It colocalizes with opioid receptors and participates in the modulation of food palatability and ingestion. CB1 receptor inverse agonist/antagonist rimonabant was used as a weight loss drug but was withdrawn from the market for increasing the risk of psychiatric side-effects (29).…”