Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor ‘silent antagonist’

Gardner, Andrew J.; Mallet, Paul E.

doi:10.1016/j.ejphar.2005.11.032

Cited by 62 publications

(55 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AM4113 also produced a significant suppression of spontaneous locomotion when administered alone. This observation is consistent with effects that were previously reported for O-2050 (Gardner and Mallet, 2006), as well as for the antagonist/ inverse agonists AM251 (McLaughlin et al, 2005a) and SR141716A (Järbe et al, 2002). The ability of a CB1 antagonist to inhibit motor activity may seem paradoxical, considering that CB1 agonists generally reduce motor activity (McLaughlin et al, 2005b).…”

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Sink

McLaughlin

Wood

et al. 2007

Neuropsychopharmacol

143

193

View full text Add to dashboard Cite

Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dosedependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists. Neuropsychopharmacology (2008) 33, 946-955;

show abstract

Section: Discussionsupporting

confidence: 90%

“…In view of the fact that SR141716 and AM251 can act as inverse agonists, it remains possible that the feeding suppression induced by neutral antagonists (eg Gardner and Mallet, 2006) would not be accompanied by behavioral signs of nausea. For this reason, it is important to evaluate novel CB1 neutral antagonists.…”

Section: Introductionmentioning

confidence: 99%

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

Sink

McLaughlin

Wood

et al. 2007

Neuropsychopharmacol

143

193

View full text Add to dashboard Cite

show abstract

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…Compounds that block the CB1 cannabinoid receptor have generated a great deal of interest as putative appetite suppressants [2,5,6,8,11,21,[26][27][28]. 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.…”

Section: Introductionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Hodge

Bow

Plyler

et al. 2008

Behavioural Brain Research

View full text Add to dashboard Cite

Cannabinoid CB1 inverse agonists such as rimonabant and AM 251 hold therapeutic promise as appetite suppressants, but the extent to which non-motivational factors contribute to their anorectic effects is not fully known. Examination of the behavioral satiety sequence (BSS) in rats, the orderly progression from eating to post-prandial grooming and then resting, has revealed that these compounds preserve the order of events but differ markedly from natural satiation. The most notable difference is that grooming (particularly scratching) is profoundly enhanced at anorectic doses, while eating and resting are diminished, raising the possibility that the anorectic effect is simply secondary to the grooming effect. In the current design, the neutral CB1 antagonist AM 4113, which has been found to lack some of the undesirable effects of AM 251, produced nearly identical effects on the BSS as AM 251. The possibility that competition from enhanced grooming could account for the anorectic effect of AM 4113 was examined by yoking the pattern of disruptions caused by grooming in the AM 4113-treated group to forced locomotion in a different group fed in a modified running wheel. This response competition did not significantly reduce food intake. It was concluded that AM 4113, a CB1 neutral antagonist, produces the same effects on the BSS as AM 251, but that response competition from enhanced grooming may not be a sufficient explanation for the anorectic effects of CB1 antagonists/inverse agonists.

show abstract

CB1 receptor inverse agonist pharmacotherapy for metabolic disorders

Fong

Addy

Erondu

et al. 2009

Drug Development Research

View full text Add to dashboard Cite

The cannabinoid-1 receptor (CB1R) has been implicated in the control of energy balance based on its anatomical localization, the interaction among the endocannabinoid system and other transmitter systems, and the appetite-enhancing effect of tetrahydrocannabinol. Recent development of CB1R inverse agonists indicated that these agents inhibit food intake, increase energy expenditure, and reduce fat mass. This article reviews the preclinical and clinical efficacy of several CB1R inverse agonists and provides a perspective on the use of CB1R inverse agonists in studies of obesity and metabolic disorders. The compounds reviewed here are no longer in clinical development for obesity. Drug Dev Res 70 : 566-576, 2009.

show abstract

Suppression of feeding, drinking, and locomotion by a putative cannabinoid receptor ‘silent antagonist’

Cited by 62 publications

References 14 publications

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

The Novel Cannabinoid CB1 Receptor Neutral Antagonist AM4113 Suppresses Food Intake and Food-Reinforced Behavior but Does not Induce Signs of Nausea in Rats

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

CB1 receptor inverse agonist pharmacotherapy for metabolic disorders

Contact Info

Product

Resources

About