A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

Cluny, N. L.; Vemuri, V. Kiran; Chambers, AP; Limebeer, Cheryl L.; Bedard, Holly; Wood, Jeff T.; Lutz, Beat; Zimmer, Andreas; Parker, Lucy Anne; Makriyannis, A.; Sharkey, Keith A.

doi:10.1111/j.1476-5381.2010.00908.x

Cited by 160 publications

(156 citation statements)

References 56 publications

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“…Some of these drugs, such as the peripherally restricted CB 1 R inverse agonist JD5037 and the CB 1 R antagonist AM6545 have been shown to reduce obesity, reverse leptin resistance and improve hepatic steatosis, dyslipidemia and insulin resistance in genetically and diet-induced obese mice (63,119,120). These are quite important observations, because they imply that the blockade of CNS CB 1 Rs is not required for the treatment of metabolic disease.…”

Section: The Ecs and Metabolic Disorders In Humansmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Simon

Cota

2017

European Journal of Endocrinology

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The endocannabinoid system (ECS), including cannabinoid type 1 and type 2 receptors (CB 1 R and CB 2 R), endogenous ligands called endocannabinoids and their related enzymatic machinery, is known to have a role in the regulation of energy balance. Past information generated on the ECS, mainly focused on the involvement of this system in the central nervous system regulation of food intake, while at the same time clinical studies pointed out the therapeutic efficacy of brain penetrant CB 1 R antagonists like rimonabant for obesity and metabolic disorders. Rimonabant was removed from the market in 2009 and its obituary written due to its psychiatric side effects. However, in the meanwhile a number of investigations had started to highlight the roles of the peripheral ECS in the regulation of metabolism, bringing up new hope that the ECS might still represent target for treatment. Accordingly, peripherally restricted CB 1 R antagonists or inverse agonists have shown to effectively reduce body weight, adiposity, insulin resistance and dyslipidemia in obese animal models. Very recent investigations have further expanded the possible toolbox for the modulation of the ECS, by demonstrating the existence of endogenous allosteric inhibitors of CB 1 R, the characterization of the structure of the human CB 1 R, and the likely involvement of CB 2 R in metabolic disorders. Here we give an overview of these findings, discussing what the future may hold in the context of strategies targeting the ECS in metabolic disease.

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Section: The Ecs and Metabolic Disorders In Humansmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Simon

Cota

2017

European Journal of Endocrinology

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“…This alongside also led to the termination of development of other CB 1 receptor blockers like taranabant and otanabant. 17,18 Still the interest in the potential of CB 1 antagonists called the peripherally restricted CB 1 receptor antagonists is retained and several such compounds are being synthesized and developed. These compounds will attain lower brain concentrations and will be free of the aversive side effects seen with rimonabant.…”

Section: Appetite Emesis and Obesitymentioning

confidence: 99%

“…These compounds will attain lower brain concentrations and will be free of the aversive side effects seen with rimonabant. [17][18][19] A novel peripherally active cannabinoid receptor antagonist, AM6545, which is more selective for CB 1 than CB 2 was tested in rodents to evaluate its effect on food intake and body weight. This agent showed limited brain permeability and dose dependently reduced food intake and inhibited body weight gain in rodents.…”

Section: Appetite Emesis and Obesitymentioning

confidence: 99%

“…This agent showed limited brain permeability and dose dependently reduced food intake and inhibited body weight gain in rodents. 17 Hence CB 1 receptor antagonists designed to have limited brain permeability hold a promising future in weight management.…”

Section: Appetite Emesis and Obesitymentioning

confidence: 99%

“…Therefore selectively targeting CB 1 receptors with agents lacking brain penetrance may prove to be an effective treatment option in such patients. 67,68 The role of CB 2 receptors on adipose tissue inflammation was also evaluated. It was seen that treatment with CB 2 selective agonist in obese mouse model, led to increase in insulin resistance and liver steatogenesis associated with obesity.…”

Section: Liver Diseasesmentioning

confidence: 99%

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Cannabinoids and their medicinal potential

Tikoo¹,

Sharma²,

Gupta³

2012

Int J Basic Clin Pharmacol

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Cannabis sativa L preparations have been used therapeutically since many years. Inspite of their medicinal value, the danger of its abusive potential led to the ban on its use in clinical practice in many countries. The recent research and in depth knowledge about the cannabinoid system which throw a light on their disease management potential has paved way for the cannabinoids to become a new therapeutic focus of attention. Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors which include CB1, predominantly expressed in the brain and CB2 which is primarily found in the cells of the immune system. Despite the addictive properties of cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases such as anorexia, pain, inflammation, obesity, cardiovascular disorders, neurodegenerative diseases, cancer, gastrointestinal diseases, hepatic disorders, skin related diseases, respiratory disorders like asthma and eye diseases like glaucoma have suggested cannabinoid agonists/ antagonists/ cannabinoids related compounds as potential treatment options. Developments of new specific ligands for the cannabinoid receptors are now underway and it needs to be seen, if in future, they can prove to be a boon for the medical world. The paper reviews the current understanding of the cannabinoid receptors, their ligands and their possible role in various diseases supported by preclinical and clinical studies. [Int J Basic Clin Pharmacol 2012; 1(2.000): 48-59

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Endocannabinoid System: An Update

Battista

Maccarrone

Bari

2017

Encyclopedia of Life Sciences

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The endocannabinoid system (ECS) is nowadays considered as an important neurotransmitter system and, although the chemistry, biochemistry and pharmacology of endocannabinoids (eCBs) have been widely investigated, quite some pieces are still missing to fully understand how this system works. The discovery of anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) dates back to the beginning of 1990 and, since then, their molecular targets, biosynthetic and catabolic enzymes have been identified. In addition, selective pharmacological and genetic tools have been developed both to explore alternative metabolic routes and to produce eCB‐based drugs as therapeutics for the prevention/treatment of a variety of diseases. In this article, we will review the metabolic pathways of eCBs, and the latest advances on their potential receptor targets. Key Concepts The endocannabinoid system is an endogenous network including endocannabinoids, a complex array of receptors, biosynthetic and hydrolytic enzymes, as well as membrane transporters. Endocannabinoids are derivatives of the arachidonic acid. The two most important endocannabinoid transmitters, anandamide and 2‐arachidonoylglycerol, are produced and eliminated through several enzyme pathways. Endocannabinoids play their main roles by targeting both cannabinoid and other membrane and nuclear receptors. The binding of endocannabinoids to cannabinoid, vanilloid and peroxisome proliferator‐activated receptors triggers several signal transduction pathways. The endocannabinoid system is a pleiotropic signalling system that is widely distributed in the central and peripheral nervous systems. Alterations of circulating endocannabinoids levels are involved in the dysregulation of activity of important physiological systems. A deep knowledge of the endocannabinoid system signalling might be translated into the development of pathway‐selective drugs for therapeutic benefit.

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A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

Cited by 160 publications

References 56 publications

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

MECHANISMS IN ENDOCRINOLOGY: Endocannabinoids and metabolism: past, present and future

Cannabinoids and their medicinal potential

Endocannabinoid System: An Update

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