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

Anandamide (arachidonoyl ethanol amide, AEA) is an endocannabinoid, acting on CB1 and CB2 receptors. Elevated plasma AEA concentrations in humans have been associated amongst others with obesity, psychological disorders and miscarriage. The occurrence in human plasma of ethanol amides of other unsaturated and saturated fatty acids, including oleic acid and palmitic acid, has also been reported. Most data available on anandamide and other fatty acid ethanol amides (FAEA) until now have been generated by using the LC-MS/MS methodology. Here, we describe a stable-isotope dilution GC-MS/MS method for the quantitative determination of AEA, oleic acid ethanol amide (OEA) and palmitic acid ethanol amide (PEA) in human plasma using their stable-isotope labeled analogs as internal standards. Other FAEA were found in plasma and their concentration was estimated. The present method involves a single solvent extraction of FAEA and their internal standards from plasma (50-1000 microl) with toluene, derivatization to the pentafluorobenzamide pentafluoropropionyl derivatives (FAEA-PFBz-PFP), and simultaneous quantification by selected reaction monitoring of the carboxylate anions produced by collision-induced dissociation of the parent ions [M-PFBz](-). The present method was fully validated for anandamide. Thus, accuracy and imprecision of the method were within the range of 100+/-20% and less than 20%, respectively, in the range investigated (0-4 nM). Mean overall recovery was 90+/-3%. The LOQ and LOD values of the method were determined to be 0.25 nM of added AEA in plasma samples and 400 amol of injected AEA-PFBz-PFP derivative, respectively. In plasma of 16 healthy individuals AEA concentration was measured to be 1.35+/-0.32 nM. This finding is concordant to literature AEA plasma concentrations as measured by LC-MS/MS. The plasma concentrations of OEA, PEA and other FAEA are higher than that of AEA. This GC-MS/MS method is straightforward, accurate, precise, highly specific for FAEA and useful in basic and clinical research.
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PMID:Targeted stable-isotope dilution GC-MS/MS analysis of the endocannabinoid anandamide and other fatty acid ethanol amides in human plasma. 1941 83

Anandamide (N-arachidonoylethanolamine, AEA) or its metabolites participate in energy balance mainly through feeding modulation. In addition, AEA has been found to increase 3T3-L1 adipocyte differentiation process. In this study, the effect of AEA, R(+)-methanandamide (R(+)-mAEA), URB597, and indomethacin on primary rat adipocyte differentiation was evaluated by a flow cytometry method and by Oil Red-O staining. Reverse transcription-PCR and western blotting analysis were performed in order to study the effect of AEA on peroxisome proliferator-activated receptor (PPAR)gamma2, cannabinoid receptors (CBRs), fatty acid amidohydrolase (FAAH), and cyclooxygenase-2 (COX-2) expression, during the differentiation process. AEA increased adipocyte differentiation in primary cell cultures in a concentration- and time-dependent manner and induced PPARgamma2 gene expression, confirming findings with 3T3-L1 cell line. CB1R, FAAH, and COX-2 expression was also increased while CB2R expression was decreased. Inhibition of FAAH and COX-2 attenuated the AEA-induced differentiation. Our findings indicate that AEA regulates energy homeostasis not only by appetite modulation but may also regulate adipocyte differentiation and phenotype.
Obesity (Silver Spring) 2009 Oct
PMID:Anandamide increases the differentiation of rat adipocytes and causes PPARgamma and CB1 receptor upregulation. 1954 11

Cannabinoid CB1 receptors have been the avenue of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of substituted pyrimidines based on chemical structure of Merck's taranabant, a cannabinoid CB1 receptor inverse agonist. Noticeably, N4-((2S,3S)-3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-yl)-N6-butylpyrimidine-4,6-diamine (13b) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50)=16.3nM, CB2/CB1=181.6).
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PMID:Substituted pyrimidines as cannabinoid CB1 receptor ligands. 1959 76

The endocannabinoid system (ECS) is a lipid signalling system, comprising of the endogenous cannabis-like ligands (endocannabinoids) anandamide (AEA) and 2-arachidonoylglycerol (2-AG), which derive from arachidonic acid. These bind to a family of G-protein-coupled receptors, called CB1 and CB2. The cannabinoid receptor 1 (CB1R) is distributed in brain areas associated with motor control, emotional responses, motivated behaviour and energy homeostasis. In the periphery, the same receptor is expressed in the adipose tissue, pancreas, liver, GI tract, skeletal muscles, heart and the reproduction system. The CB2R is mainly expressed in the immune system regulating its functions. Endocannabinoids are synthesized and released upon demand in a receptor-dependent way. They act as retrograde signalling messengers in GABAergic and glutamatergic synapses and as modulators of postsynaptic transmission, interacting with other neurotransmitters. Endocannabinoids are transported into cells by a specific uptake system and degraded by the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The ECS is involved in various pathophysiological conditions in central and peripheral tissues. It is implicated in the hormonal regulation of food intake, cardiovascular, gastrointestinal, immune, behavioral, antiproliferative and mammalian reproduction functions. Recent advances have correlated the ECS with drug addiction and alcoholism. The growing number of preclinical and clinical data on ECS modulators is bound to result in novel therapeutic approaches for a number of diseases currently treated inadequately. The ECS dysregulation has been correlated to obesity and metabolic syndrome pathogenesis. Rimonabant is the first CB1 blocker launched to treat cardiometabolic risk factors in obese and overweight patients. Phase III clinical trials showed the drug's ability to regulate intra-abdominal fat tissue levels, lipidemic, glycemic and inflammatory parameters. However, safety conerns have led to its withrawal. The role of endocannabinoids in mammalian reproduction is an emerging research area given their implication in fertilization, preimplantation embryo and spermatogenesis. The relevant preclinical data on endocannabinoid signalling open up new perspectives as a target to improve infertility and reproductive health in humans.
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PMID:Endocannabinoid system: An overview of its potential in current medical practice. 1967 19

Endogenous cannabinoids are ubiquitous lipid-signaling molecules able to partially mimic the actions produced by Delta(9)-tetrahydrocannabinol, the compound responsible for most of the psychological effects of marijuana. Endocannabinoids are derived from arachidonic acid and are involved in many physiological effects. This family of substances includes anandamide (arachidonylethanolamide), 2-arachydonylglycerol, noladin ether and virodhamine. The interaction of these substances with CB1 and CB2 receptors results in most of their biological effects. The endocannabinoid system is involved in the pathogenesis of the cardiovascular dysfunction occurring in advanced liver disease and also plays a role in the pathogenesis of portal hypertension and liver fibrosis. Moreover, this system is also altered in other processes associated with hepatic dysfunction, including encephalopathy, obesity and steatosis. These findings indicate that the endocannabinoid system may open new avenues for the therapeutic regulation of fibrosis and portal hypertension in advanced liver disease.
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PMID:[Endogenous cannabinoids in liver disease: Many darts for a single target]. 1975 27

Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of pentacycle derivatives. Five of the new compounds which displayed high in vitro rCB1 binding affinities were assayed for binding to hCB2 receptor. Noticeably, 2-(5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole (16l) demonstrated good binding affinity and decent selectivity for rCB1 receptor (IC(50)=1.72 nM, hCB2/rCB1=142).
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PMID:Pentacycle derivatives as cannabinoid CB1 receptor ligands. 1985 Apr 73

Non alcoholic steatohepatitis (NASH) has gained a lot of attention recently due to the increased prevalence of diabetes, obesity, and hyperlipedemia. The endogenous compounds, endocannabinoids (ECBs), bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. Recently, two G-proteins coupled, and specific receptors, to cannabinoids, CB1 & CB2, which act via adenylate cyclase and calcium channels, were described. In this brief review, we shed light on the possible relation between NASH and these proteins. It has been hypothesized that ECBs regulate peripheral lipogenesis. Some studies suggest that in CB1-deficient mice there is complete resistance to the development of diet-induced hepatic steatosis, while wild-type mice showed remarkable hepatic steatosis after 3 and 14 weeks of high-fat diet. Based on these results and others, the hepatic ECB system may be a target for the treatment of NASH. The CB1 antagonist, Rimonabant, will shortly be approved for the treatment of obesity and may thus reduce the necessity for bariatric surgery.
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PMID:Endocannabinoids and non-alcoholic steatohepatitis. 1985 84

The endocannabinoid system (ECS) represents one of the most important physiologic systems involved in organism homeostasis, having various implications upon individual behavior and metabolic phenotype. It is composed of cannabinoid receptors CB1 and CB2, and their genes (CNR1 and CNR2), their endogenous ligands and the enzymes which mediate endogenous ligands' biosynthesis and degradation. Anandamide and 2-arachidonoylglycerol are two endogenous agonists of the cannabinoid receptors. It is considered that ECS connects physical and emotional response to stress with appetite and energy balance, functioning like an after stress recovery system which remains inactive in repose physiologic conditions. It is involved in several physiologic processes like nociception, motor control, memory, learning, appetite, food intake and energy balance. This review analyzes the implication of 11 polymorphisms of CNR1 gene in the modulation of the ECS metabolic and central effects. A lot of studies show that rs12720071, rs1049353, rs806381, rs10485170, rs6454674, rs2023239 polymorphisms are associated with metabolic effects. From them rs12720071, rs104935, rs6454674, rs2023239 polymorphisms are also associated with central effects of ECS (substance addiction, impulsivity, resistance to antidepressive treatment). Other studies indicate that rs806368, rs1535255, (AAT)9,(AAT)12 and (AAT)n are correlated only with central effects (schizophrenia, substance addiction, impulsivity, Parkinson syndrome). The discovery of ECS and its signaling pathways opens a door towards the understanding of several important physiologic processes regarding appetite, food intake, metabolism, weight gain, motor control, memory, learning, drug addiction and nociception. The detailed analysis and validation of the ECS functioning can bring us very close to the discovery of new diagnosis and treatment methods for obesity, drugs abuse and numerous psychic diseases.
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PMID:The implication of CNR1 gene's polymorphisms in the modulation of endocannabinoid system effects. 1988 64

Much progress has been achieved in cannabinoid research. A major breakthrough in marijuana-cannabinoid research has been the discovery of a previously unknown but elaborate endogenous endocannabinoid system (ECS), complete with endocannabinoids and enzymes for their biosynthesis and degradation with genes encoding two distinct cannabinoid (CB1 and CB2) receptors (CBRs) that are activated by endocannabinoids, cannabinoids, and marijuana use. Physical and genetic localization of the CBR genes CNR1 and CNR2 have been mapped to chromosome 6 and 1, respectively. A number of variations in CBR genes have been associated with human disorders including osteoporosis, attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), drug dependency, obesity, and depression. Other family of lipid receptors including vanilloid (VR1) and lysophosphatidic acid (LPA) receptors appear to be related to the CBRs at the phylogenetic level. The ubiquitous abundance and differential distribution of the ECS in the human body and brain along with the coupling to many signal transduction pathways may explain the effects in most biological system and the myriad behavioral effects associated with smoking marijuana. The neuropharmacological and neuroprotective features of phytocannabinoids and endocannabinoid associated neurogenesis have revealed roles for the use of cannabinoids in neurodegenerative pathologies with less neurotoxicity. The remarkable progress in understanding the biological actions of marijuana and cannabinoids have provided much richer results than previously appreciated cannabinoid genomics and raised a number of critical issues on the molecular mechanisms of cannabinoid induced behavioral and biochemical alterations. These advances will allow specific therapeutic targeting of the different components of the ECS in health and disease. This review focuses on these recent advances in cannabinoid genomics and the surprising new fundamental roles that the ECS plays in the retrograde signaling associated with cannabinoid inhibition of neurotransmitter release to the genetic basis of the effects of marijuana use and pharmacotherpeutic applications and limitations. Much evidence is provided for the complex CNR1 and CNR2 gene structures and their associated regulatory elements. Thus, understanding the ECS in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.
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PMID:Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications. 1989 83

Numerous research groups have been engaged in searching for novel CB1 receptor antagonists, since SR141716A (rimonabant), a CB1 receptor antagonist, proved to be efficacious in human for the treatment of obesity. In the present study, a series of 1,2,4-triazole-containing diarylpyrazolyl carboxamides based on the 1,5-diarylpyrazole template of rimonabant, was synthesized and tested for CB1 receptor binding affinity. The structure-activity relationship studies demonstrated that incorporation of 1,2,4-triazole ring onto the pyrazole scaffold via a methylene linker led to a significant improvement for CB1 receptor binding affinity. Importantly, these analogues also exhibited excellent selectivity for CB1 receptor over CB2 receptor.
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PMID:Synthesis and structure-activity relationship of 1,2,4-triazole-containing diarylpyrazolyl carboxamide as CB1 cannabinoid receptor-ligand. 2004 37


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