Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties

Abstract

The CB1 inverse agonist/antagonist SR141716A recently has been introduced for the management of obesity (rimonabant; Acomplia) and appears to have beneficial effects. However, its utility may be hampered in some individuals by adverse effects including nausea or emesis or by mood depression. The recent development of biochemically 'neutral' antagonists such as AM4113 (Sink et al. 2007) has allowed an initial evaluation of the proposition that the adverse effects of SR141716A are associated with its inverse agonist activity. Thus far, data comparing SR141716A and AM4113 across several species indicate that both drugs produce dose-related direct effects on operant behavior within the same range of doses that serve to antagonize the behavioral and hypothermic effects of a CB1 agonist. However, initial observations suggest that AM4113 may not produce preclinical indications of nausea or emesis. Further studies with AM4113 and other novel CB1 antagonists differing in efficacy should amplify our understanding of the relationship between the pharmacological activity of CB1 antagonists and their behavioral effects. KeywordsSR141716A; rimonabant; AM4113; AM4054; inverse agonism; neutral antagonism; behavior; hypothermia A rapid succession of events in the first half of the 1990s including the discovery of the cannabinoid-1 (CB1) receptor and the isolation and synthesis of its endogenous ligands anandamide and 2-AG, energized the explosion of scientific interest in cannabinoid pharmacology and the development of novel ligands, including those that produced Δ 9 THClike effects and those could counter, i.e., antagonize, the effects of Δ 9 THC and other CB1 agonists at the CB1 receptor. It is interesting that, notwithstanding the acknowledged medicinal value of cannabis products with CB1 agonist actions, the first major therapeutic agent to emerge from these research efforts has been the CB1 antagonist/inverse agonist SR141716A (rimonabant; [1]). Perhaps it is not surprising that its initial therapeutic targets have been based a The preparation of this manuscript and portions of the work described herein were supported under NIH/NIDA DA19205 b Portions of the work described herein have been presented previously at the 2005 meeting of the College on Problems of Drug Dependence in Orlando, FL and at the

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].…”

“…For instance, the CB1 inverse agonist AM 251 induces conditioned taste avoidance and conditioned gaping, both markers of nausea, at anorectic doses [22]. The neutral antagonist AM 4113 was later found to have no effect on conditioned gaping over a dose range that inhibited food intake [3,28]. This finding had two promising implications: first, CB1 neutral antagonists may lack the effect of nausea that has been shown with CB1 inverse agonists in rats [22] and humans [24]; and secondly, that the reduction in food intake produced by CB1 blockade is not likely to be due to nausea, as these appear to be dissociable mechanisms.…”

“…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].…”

The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs

“…In case of NGF or eCB alteration by any psychotropic medication, the CB 1 receptor neutral antagonist AM4113 (N-piperidin-1-yl-2,4-dichlorophenyl-1H-pyrazole-3-carboxamide analog, Center for Drug Discovery, Northeastern University, USA) was dissolved in dimethylsulfoxide (Sigma-Aldrich, Germany), Tween-80 (Sigma-Aldrich, Germany), and 0.9% saline in a 1:1:8 ratio and injected i.p. at doses of 1, 3, and 5.6 mg/kg (Bergman et al 2008;Chambers et al 2007;Sink et al 2008) 30 min prior to the administration of psychotropic drug in order to investigate the possible implication of the CB 1 receptors in this regard. All drugs were injected at a total volume of 1 ml/kg.…”