The neutral cannabinoid CB1 receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat

Abstract

The aim of this study was to determine if the neutral cannabinoid CB1 receptor antagonist, AM4113, regulates body weight in the rat via changes in food intake. We confirmed that the AM4113-induced reduction in food intake is mediated by CB1 receptors using CB1 receptor knockout mice. In rats, intraperitoneally administered AM4113 (2, 10 mg kg−1) had a transient inhibitory effect on food intake, while body weight gain was suppressed for the duration of the study. AM4113-induced hypophagia was no longer observed once the inhibitory effect of AM4113 on body weight stabilized, at which time rats gained weight at a similar rate to vehicle-treated animals, yet at a lower magnitude. Pair-feeding produced similar effects to treatment with AM4113. Food intake and body weight gain were also inhibited in rats by oral administration of AM4113 (50 mg kg−1). Dual energy x-ray absorptiometry (DEXA) was used to measure lean and fat mass. The AM4113 treated group had 29.3 ± 11.4 % lower fat mass than vehicle treated rats; this trend did not reach statistical significance. There were no differences in circulating levels of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG), glucose, triglycerides, or cholesterol observed between treatment groups. Similarly, 2-AG hypothalamic levels were not modified by AM4113 treatment. These data suggest that blockade of an endocannabinoid tone acting at CB1 receptors induces an initial, transient reduction in food intake which results in long-term reduction of body weight gain.

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).…”

Anti - Obesity Drugs : Present and Future

“…Following a meal the reverse occurs, with high levels of glucose, insulin, CCK and reduced ghrelin levels leading to increases in pro-opiomelanocortin (POMC), in turn increasing α-melanocyte stimulating hormone (α-MSH) release and decreasing MCH/ORX activity, leading to satiation and a termination of feeding. 13,14 Combination Therapy: Qnexa It consist of lower doses of topiramate and phentermine. Topiramate has been approved for migraine prophylaxis and the treatment of seizure disorders.…”

“…However, the study did not report the values for the higher-dose treatment group. 13 The most frequent adverse events were nasopharyngitis, upperrespiratory infections, sinusitis, and headache. Laboratory data also show mild decreases in hematocrit, hemoglobin, and red blood cell count, although all of these remained within the normal ranges.…”

“…12 Shinogi has completed the phase II trials, and planning for phase III trials is under way. 13 Obinepitide: Obinepitide is a synthetic analog of two naturally occurring human hormones: PYY3-36 and pancreatic polypeptide. These hormones are normally released during a meal and are known to play a role in the regulation of food intake and appetite, acting as satiety signals.…”