A neutral CB₁ receptor antagonist reduces weight gain in rat

Abstract

Cannabinoid (CB)1 receptor inverse agonists inhibit food intake in animals and humans but also potentiate emesis. It is not clear whether these effects result from inverse agonist properties or from the blockade of endogenous cannabinoid signaling. Here, we examine the effect of a neutral CB1 antagonist, AM4113, on food intake, weight gain, and emesis. Neutral antagonist and binding properties were confirmed in HEK-293 cells transfected with human CB1 or CB2 receptors. AM4113 had no effect on forskolin-stimulated cAMP production at concentrations up to 630 nM. The Ki value of AM4113 (0.80 +/- 0.44 nM) in competitive binding assays with the CB1/2 agonist [3H]CP55,940 was 100-fold more selective for CB1 over CB2 receptors. We determined that AM4113 antagonized CB1 receptors in brain by blocking hypothermia induced by CP55,940. AM4113 (0-20 mg/kg) significantly reduced food intake and weight gain in rat. Compared with AM251, higher doses of AM4113 were needed to produce similar effects on food intake and body weight. Unlike AM251 (5 mg/kg), a highly anorectic dose of AM4113 (10 mg/kg) did not significantly potentiate vomiting induced by the emetic morphine-6-glucoronide. We show that a centrally active neutral CB1 receptor antagonist shares the appetite suppressant and weight loss effects of inverse agonists. If these compounds display similar properties in humans, they could be developed into a new class of antiobesity agents.

The cannabinoid CB1 receptor inverse agonist AM 251 and antagonist AM 4113 produce similar effects on the behavioral satiety sequence in rats

“…This is consistent with previous reports on the CB1 inverse agonists SR 141716A [29] and AM 251 [30], but the current paper is believed to be the first report of these effects by a CB1 neutral antagonist that has been demonstrated to lack intrinsic activity [3,7,28]. For both compounds, fur cleaning, biting, and scratching are increased and predominate over eating and resting at anorectic doses.…”

“…However, the mechanism by which these compounds reduce food intake is not entirely understood, and it is possible that the reduction in food intake seen with drugs such as the CB1 inverse agonists rimonabant (a.k.a. SR 141716A; [22,25]), AM 251 [12,21], AM 1387 [23], and the neutral antagonists O-2050 [11] and AM 4113 [3,7,28] may result at least in part from non-motivational actions. For instance, the CB1 inverse agonist AM 251 induces conditioned taste avoidance and conditioned gaping, both markers of nausea, at anorectic doses [22].…”

“…Experiments 1 and 2 were designed to test the BSS effects of the CB1 inverse agonist AM 251 and the CB1 neutral antagonist AM 4113, respectively. As CB1 neutral antagonists such as O-2050 and AM 4113 are known to reduce food intake [3,7,11,28], it is likely that blockade of endocannabinoid tone, rather than CB1 inverse agonist activity, is sufficient to suppress feeding. However, as CB1 antagonists may not produce effects such as nausea [28], it is possible that AM 4113 would not elicit the disruptions on the BSS that have been shown with AM 251 [30].…”

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

“…Taranabant and rimonabant have been shown in numerous studies to exhibit inverse agonist properties (Figure 1). [11][12][13][14][15][16][17] In the literature, some authors have continued to use the term antagonist, and some authors have used the term antagonist/inverse agonist to describe rimonabant and taranabant. It should be pointed out here that the term antagonist emphasizes its ability to antagonize the agonist effect, and the term inverse agonist emphasizes its ability to inhibit CB1R activity in the absence of agonist.…”

Cannabinoid Discrimination and Antagonism by CB1Neutral and Inverse Agonist Antagonists

“…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).…”