Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Over the past 15 years, research on the endogenous cannabinoid (CB) system-now usually referred to as the endocannabinoid system (ECS)-has identified the significant effects of the ECS on the regulation of food intake and lipid and glucose metabolism in animals and humans. Endocannabinoids are endogenous lipids capable of binding to endogenous CB1 and CB2 receptors. CB1 receptors are present in the hypothalamic nuclei, which are involved in the control of energy balance and body weight, and in the mesolimbic system, which mediates the motivation to consume palatable food, as well as in adipocytes, the gut, and the liver. In the recent Rimonabant in Obesity (RIO)-Europe study, treatment with the first CB1 receptor antagonist, rimonabant, led to sustained, clinically meaningful weight loss and a reduction in waist circumference. Patients treated with rimonabant also demonstrated statistically significant improvement in high-density lipoprotein cholesterol levels, triglyceride levels, and insulin resistance, as well as a reduced overall prevalence of metabolic syndrome. Results of this and other studies support the role of endocannabinoids in the development and maintenance of obesity. In addition, these findings suggest that CB1 receptor antagonists such as rimonabant may offer a potential new approach to managing obesity and associated cardiometabolic risk factors.
 ...
PMID:Reducing cardiometabolic risk through selective antagonism of CB1 receptors. 1794 64

Although rimonabant has been approved for use in several countries, the Food and Drug Administration has expressed concern about the potential for adverse neurologic and psychiatric effects, considering the widespread distribution of CB1 receptors in the brain. While more research is clearly needed, the clinical evidence shows that CB1-receptor blockade with rimonabant improves multiple cardiovascular and metabolic variables, including body weight and waist circumference, HDL-C, triglycerides, and glucose metabolism. Furthermore, these effects, which are probably mediated by both peripheral and central actions in the ECS, appear to be greater than the improvements that would be expected from weight loss alone. There are multiple ongoing and planned studies with rimonabant as well as several other CB-receptor blockers (e.g., taranabant, CP-945,598). While diet and exercise are the cornerstones of cardiometabolic risk-factor reduction, improved pharmacotherapies are urgently needed. The ECS has provided us with new insights and a promising new avenue for the management of obesity and its associated cardiometabolic risk factors.
 ...
PMID:The endocannabinoid system: novel pathway for cardiometabolic Risk-factor reduction. 1804 36

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 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.
 ...
PMID:Some effects of CB1 antagonists with inverse agonist and neutral biochemical properties. 1807 56

Endogenous signaling lipids ("endocannabinoids") functionally related to Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (Cannabis), are important biomediators and metabolic regulators critical to mammalian (patho)physiology. The growing family of endocannabinoids, along with endocannabinoid biosynthetic and inactivating enzymes, transporters, and at least two membrane-bound, G-protein coupled receptors, comprise collectively the mammalian endocannabinoid signaling system. The ubiquitous and diverse regulatory actions of the endocannabinoid system in health and disease have supported the regulatory approval of natural products and synthetic agents as drugs that alter endocannabinoid-system activity. More recent data support the concept that the endocananbinoid system may be modulated for therapeutic gain at discrete pharmacological targets with safety and efficacy. Potential medications based on the endocannabinoid system have thus become a central focus of contemporary translational research for varied indications with important unmet medical needs. One such indication, obesity, is a global pandemic whose etiology has a pathogenic component of endocannabinoid-system hyperactivity and for which current pharmacological treatment is severely limited. Application of high-affinity, selective CB1 cannabinoid receptor ligands to attenuate endocannabinoid signaling represents a state-of-the-art approach for improving obesity pharmacotherapy. To this intent, several selective CB1 receptor antagonists with varied chemical structures are currently in advanced preclinical or clinical trials, and one (rimonabant) has been approved as a weight-management drug in some markets. Emerging preclinical data suggest that CB1 receptor neutral antagonists may represent breakthrough medications superior to antagonists/inverse agonists such as rimonabant for therapeutic attenuation of CB1 receptor transmission. Since obesity is a predisposing condition for the cluster of cardiovascular and metabolic derangements collectively known as the metabolic syndrome, effective endocannabinoid-modulatory anti-obesity therapeutics would also help redress other major health problems including type-2 diabetes, atherothrombosis, inflammation, and immune disorders. Pressing worldwide healthcare needs and increasing appreciation of endocannabinoid biology make the rational design and refinement of targeted CB1 receptor modulators a promising route to future medications with significant therapeutic impact against overweight, obesity, obesity-related cardiometabolic dysregulation, and, more generally, maladies having a reward-supported appetitive component.
 ...
PMID:Pharmacotherapeutic targeting of the endocannabinoid signaling system: drugs for obesity and the metabolic syndrome. 1815 57

--Obesity is an important healthcare issue. --Recent research has led to insights into the role of the endocannabinoid system in the regulation of body weight. --Rimonabant is a CB1-endocannabinoid-receptor antagonist. --Four trials were published recently on the efficacy and safety of rimonabant in the treatment of people with obesity. --When combined with a hypocaloric diet, rimonabant 20 mg/day was more effective than placebo in achieving and maintaining weight loss. In addition, treatment with rimonabant had beneficial effects on insulin resistance, HDL-cholesterol and hypertriglyceridaemia. --There is concern regarding the increased incidence of depression during treatment. --Whether the beneficial effects of rimonabant on weight reduction and cardiovascular risk factors translate into a reduction in cardiovascular morbidity and mortality remains to be established in large phase III trials.
 ...
PMID:[The endocannabinoid system, overweight, and the CB1-endocannabinoid-receptor antagonist rimonabant]. 1816 Dec 63

The endocannabinoid (EC) system is a physiological system with an important regulatory role in numerous biological functions, both centrally and peripherally. In certain conditions it can become hyperactive and induce a variety of disorders. The system has two receptor types, designated CB1 and CB2 (present respectively in the CNS and the periphery), as well as endogenous ligands (AEA and 2-AG) and equipment for transporting, synthesizing and degrading them. The discovery of specific CB1 antagonists has opened up interesting new possibilities for the treatment of obesity, diabetes and cardiometabolic risk factors.
 ...
PMID:[Pharmacology of cannabinoid receptors]. 1822 47

After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC(50) values less than 100 nM for the CB1 receptor binding.
 ...
PMID:Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands. 1824 11

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.
 ...
PMID:CB1 cannabinoid antagonists: structure-activity relationships and potential therapeutic applications. 1828 89

GIP receptor antagonism with (Pro3)GIP protects against obesity, insulin resistance, glucose intolerance and associated disturbances in mice fed high-fat diet. Furthermore, cannabinoid CB1 receptor antagonism with AM251 reduces appetite and body weight gain in mice. The present study has examined and compared the effects of chronic daily administrations of (Pro3)GIP (25 nmol/kg body weight), AM251 (6 mg/kg body weight) and a combination of both drugs in high-fat fed mice. Daily i.p. injection of (Pro3)GIP, AM251 or combined drug administration over 22 days significantly (P<0.05 to <0.01) decreased body weight compared with saline-treated controls. This was associated with a significant (P<0.05 to <0.01) reduction of food intake in mice treated with AM251. Plasma glucose levels and glucose tolerance were significantly (P<0.05) lowered by 22 days (Pro3)GIP, AM251 or combined drug treatment. These changes were accompanied by a significant (P<0.05) improvement of insulin sensitivity in all treatment groups. In contrast, AM251 lacked effects on glucose tolerance, metabolic response to feeding and insulin sensitivity in high-fat mice when administered acutely. These data indicate that chemical blockade of GIP- or CB1-receptor signaling using (Pro3)GIP or AM251, respectively provides an effective means of countering obesity and related abnormalities induced by consumption of high-fat energy-rich diet. AM251 lacks acute effects on glucose homeostasis and there was no evidence of a synergistic effect of combined treatment with (Pro3)GIP.
 ...
PMID:Comparison of independent and combined chronic metabolic effects of GIP and CB1 receptor blockade in high-fat fed mice. 1829 59

Cannabinoid CB1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed a new series of tetrazole-biarylpyrazoles. The various analogues were efficiently prepared and bio-assayed for binding to cannabinoid CB1 receptor. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, cyclopentyl-tetrazole (9a) demonstrated good binding affinity and selectivity for CB1 receptor (IC(50)=11.6nM and CB2/CB1=366).
 ...
PMID:Tetrazole-biarylpyrazole derivatives as cannabinoid CB1 receptor antagonists. 1833 96


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>