Cannabinoid Receptors in Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance
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Rimonabant
Cannabinoid Receptor Agonists
The endocannabinoid system comprises endocannabinoid and two cloned subtypes of cannabinoid receptor, CB1 and CB2, which can stimulate appetite when activated. ompared with normal mice, the body weight and the mass of adipose tissue of CB1(-/-) mice decrease significantly. B1(-/-) mice don't develope obesity and insulin resistance even given high-fat diet. Evidence suggested that CB1 antagonists can decrease appetite and improve metabolism through central and peripheral ways. Rimonabant, a CB1 antagonist, has been in phase Ⅲ clinical trials for treatment of obesity and can decrease appetite and weight in humans. No serious side effect of rimonabant has been reported yet.
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The development of improved pharmacotherapeutics for treating cannabinoid dependence has presented many challenges. This report will discuss these challenges as well as use an animal model to study cannabinoid dependence by incorporating traditional methodologies (e.g., tetrad assay) and profiling novel cannabinoid ligands with distinct pharmacological properties/modes of action by evaluating their pharmacological effects on CB1-receptor related physiological and behavioral endpoints. Initial steps were made to characterize acutely AM2389, a CB1-receptor agonist, in the tetrad assay (i.e., locomotor activity, paw thermal stimulation, inverted screen test/catalepsy bar test and rectal temperature) as a novel approach for inducing dependence with greater potency and a prolonged functional in vivo duration of action than Δ9-THC. Cannabinoid tolerance was then evaluated with repeated administration of AM2389. Next, the effects of centrally acting antagonists, rimonabant and AM4113, and a neutral antagonist with limited acute brain penetration, AM6545, were characterized behaviorally prior to examining precipitated withdrawal. Antagonist-precipitated withdrawal was induced in cannabinoid-tolerant mice by either rimonabant or AM4113 but not by AM6545. Finally, CB1-receptor antagonist induced precipitated withdrawal was reversed by reinstating either AM2389 or Δ9-THC in cannabinoid-tolerant mice. Overall, these findings suggest that cannabinoid precipitated withdrawal may not be ascribed to the inverse agonist properties of the CB1-receptor antagonist rimonabant, but rather simply to the rapid displacement of the agonist from the CB1-receptor. Furthermore, this cannabinoid withdrawal syndrome is likely centrally mediated, since only the centrally acting CB1-receptor antagonists were able to elicit "withdrawal" responses, i.e., such responses were not induced by the purported peripherally selective CB1-receptor antagonist AM6545.
Rimonabant
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Cannabinoid receptor antagonist
Cannabinoid Receptor Agonists
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The endocannabinoid system(ECS) is consisted of endogenous cannabinoid substances and their receptors.ECS is involved in the energy homeostasis,the metabolic regulations of sugars and lipids,and the body weight control.Rimonabant is the first cannabinoid receptorⅠantagonist as a weight-reducing drug,which executes pharmacological effects by the modulation of ECS.In this article,we reviewed the physiology of cannabinoid receptor and the endogenous cannabinoid system,and the preclinical pharmacodynamics,pharmacological mechanisms,pharmacokinetics and metabolisms of rimonabant.We also introduced the relationship between the toxicity and the pharmacological actions of rimonabant,and the pharmacodynamics and pharmacological actions of taranabant,a second generation cannabinoid receptorⅠantagonist.We hope to facilitate the development of more safe and effective cannabinoid receptorⅠantagonists.
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Rimonabant
Inverse agonist
Cannabinoid Receptor Agonists
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CB1 Cannabinoid Antagonists: Structure-Activity Relationships and Potential Therapeutic Applications
During the last decade there has been a growing interest towards the modulation of the cannabinoid CB1 receptor. The identification of CB1 cannabinoid receptor antagonists has been one of the major advances in cannabinoid research. Thus, the development of these ligands has opened new therapeutic applications. Since the discovery of the first cannabinoid receptor antagonist, rimonabant, by Sanofi in 1994, a large number of structural variations within this chemical series of 1,5-diarylpyrazoles have been described. So far, all attempts to identify novel structures for CB1 antagonists have been based on one or more pharmacophoric elements of the rimonabant structure. The advanced clinical trials of rimonabant confirm the therapeutic potential value of CB1 antagonists for the treatment of obesity. In addition, the results of pharmacological and clinical studies reveal other effective pharmacotherapeutic applications. The current review will mainly focus on the structure-activity relationships that have been established for antagonists/inverse agonists that bind to the CB1 cannabinoid receptors and on their therapeutic applications.
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Purpose of review Growing evidence suggests an important role in metabolic control of the endocannabinoid system, which is composed of cannabinoid receptors, endocannabinoids, and related enzymes. In this short review, we describe the latest advances in this research field, including the antiobesity effect of the cannabinoid receptor CB1 antagonist rimonabant and the anorexic effect of N-oleoylethanolamine, an endocannabinoid-related, endogenous substance. Recent findings CB1 is expressed not only in various brain regions, including hypothalamus, but also in peripheral organs such as adipose tissue and liver. The endocannabinoid system appears to function as a physiological system regulating food intake, energy balance, and lipid metabolism through both central and peripheral mechanisms. Obesity may be associated with hyperactivity of the endocannabinoid system. Large phase III trials of rimonabant confirmed significant weight loss and waist circumference reduction in overweight and obese patients. The levels of HDL-cholesterol, triglycerides, and HbA1c were also improved. The anorexic effect of N-oleoylethanolamine was suggested to be mediated by peroxisome proliferator-activated receptor-α and the G protein-coupled receptor GPR119. Summary These results highlight the importance of an endocannabinoid tone in metabolic control and therapeutic usefulness of CB1 antagonists. Derivatives of N-oleoylethanolamine may be developed as new antiobesity drugs.
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