UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We tested two hypotheses about monoamine neurotransmitters in two strains of rats that differ in their sensitivity to obesity when eating a high-fat diet; 1) that the concentrations of norepinephrine and serotonin and of their metabolites differ in the extracellular fluid of the ventromedial hypothalamus of conscious, unrestrained Osborne-Mendel and S 5B/Pl rats, and 2) that these monoamines are altered differently between strains by a high-fat diet. The monoamines were measured by HPLC in dialysate collected by in vivo microdialysis in rats eating a semisynthetic low-fat diet (10% of kcal as fat) and again after either two or seven days of eating a high-fat diet (56% of kcal as fat). Norepinephrine, serotonin (5-HT), and 5-hydroxyindole-3-acetic acid (5-HIAA) were lower in Osborne-Mendel rats than in S 5B/Pl rats eating the low-fat diet. Norepinephrine and serotonin both increased in Osborne-Mendel rats with the onset of the high-fat diet so that Osborne-Mendel and S 5B/Pl rats no longer differed in these neurotransmitters. By day 7 of high-fat feeding, the concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-HIAA and the 5-HIAA/5-HT ratio rose in both strains. Ambient extracellular monoamines in the medial hypothalamus are lower in Osborne-Mendel rats than in S 5B/Pl rats and the response of these catecholamines to dietary fat was greater in Osborne-Mendel rats than in S 5B/Pl rats.
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PMID:Extracellular hypothalamic monoamines measured by in vivo microdialysis in a rat model of dietary fat-induced obesity. 1635 84

Weight gain is associated with the use of many psychotropic medications, including antidepressants, mood stabilizers, antipsychotic drugs, and may have serious long term consequences: it can increase health risks, specifically from overweight (BMI = 25-29.9 kg/m2) to obesity (BMI > or =30 kg/m2), according to Body Mass Index (BMI), and the morbidity associated therewith in a substantial part of patients (hypertension, coronary heart desease, ischemic stroke, impaired glucose tolerance, diabetes mellitus, dyslipidemia, respiratory problems, osteoarthritis, cancer); according to patients, psychosocial consequences such as a sense of demoralization, physical discomfort and being the target of substantial social stigma are so intolerable that they may discontinue the treatment even if it is effective. The paper reviews actual epidemiological data concerning drug induced weight gain and associated health problems in psychiatric patients : there is a high risk of overweight, obesity, impaired glucose tolerance, diabetes mellitus, premature death, in patients with schizophrenia or bipolar disorder; and the effects of specific drugs on body weight: Tricyclic Antidepressants (TCA) induced weight gain correlated positively with dosage and duration of treatment, more pronounced with amitriptyline ; Selective Serotonin Reuptake Inhibitors (SSRI) decrease transiently bodyweight during the first few weeks of treatment and may then increase bodyweight; weight gain appears to be most prominent with some mood stabilizers (lithium, valproate); atypical antipsychotics tend to cause more weight gain than conventional ones and weight gain, diabetes, dyslipidemia, seem to be most severe with clozapine and olanzapine. Conceming the underlying mechanisms of drug induced weight gain, medications might interfere with central nervous functions regulating energy balance; patients report about: increase of appetite for sweet and fatty foods or "food craving" (antidepressants, mood stabilizers, antipsychotic drugs) and weight gain despite reduced appetite which can be explained by an altered resting metabolic rate (TCA, SSRI, Monoaminoxidase Inhibitors MAO I). According to current concepts, appetite and feeding are regulated by a complex of neurotransmitters, neuromodulators, cytokines and hormones interacting with the hypothalamus, including the leptin and the tumor necrosis factor system. The pharmacologic mechanisms underlying weight gain are presently poorly understood: maybe the different activities at some receptor systems may induce it, but also genetic predisposition. Understanding of the metabolic consequences of psychotropic drugs (weight gain, diabetes, dyslipidemia) is essential: the insulin-like effect of lithium is known; treatment with antipsychotic medications increases the risk of impaired glucose tolerance and diabetes mellitus. Several management options of weight gain are available from choosing or switching to another drug, dietary advices, increasing physical activities, behavioural treatment, but the best approach seems to attempt to prevent the weight gain : patients beginning maintenance therapy should be informed of that risk, and nutritional assessment and counselling should be a routine part of treatment management, associated with monitoring of weight, BMI, blood pressure, biological parameters (baseline and three months monitoring of fasting glucose level, fasting cholesterol and triglyceride levels, glycosylated haemoglobin). Psychiatrics must pay attention to concomitant medications and individual factors underlying overweight and obesity. Weight gain has been described since the discovery and the use of the firstpsychotropic drugs, but seems to intensify with especially some of the second generation antipsychotic medications ; understanding of the side effects of psychotropic drugs, including their metabolic consequences (weight gain, diabetes, dyslipidemia) is essential for the psychiatrics to avoid on the one hand a risk of lack of compliance, a discontinuation of the pharmacological medication and also a risk of relapse and rehospitalization, and on the other hand to avoid acute life threatening events (diabetic ketoacidocetosis and non ketotic hyperosmolar coma, long term risk complications of diabetes and overweight).
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PMID:[Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management]. 1638 18

WAY-161503 ((4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one), a 5-HT(2B/C) receptor agonist, was characterized in vitro using stable Chinese hamster ovary cell lines expressing each of the human 5-HT2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([125I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([3H]mesulergine) radioligand binding to the human 5-HT2C receptor with derived Ki values of 3.3 +/- 0.9 and 32 +/- 6 nM, respectively. Relative to 5-HT2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT2A receptors ([125I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT2B receptors ([3H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT2C-receptor-coupled [3H]inositol phosphate (IP) formation and calcium mobilization with EC50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT2B agonist (EC50s of 6.9 and 1.8 nM for IP and calcium, respectively). In IP studies, WAY-161503 was a weak 5-HT(2A) partial agonist (EC50, 802 nM) yet potently stimulated calcium mobilization (EC50, 7 nM) in 5-HT2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A2-coupled arachidonic acid release in 5-HT2C receptor expressing cells albeit with lower potency (EC50, 38 nM) and efficacy (Emax, 77%) compared with activation of the PLC pathway. In vivo, WAY-161503 produced dose-dependent decreases in 2-h food intake in 24 h fasted normal Sprague-Dawley rats, diet-induced obese mice, and obese Zuker rats with ED50 values of 1.9 mg/kg, 6.8 mg/kg, and 0.73 mg/kg, respectively. The reduction in food intake in normal Sprague-Dawley rats was reversed by administration of the 5-HT2C receptor antagonist SB-242084. Following chronic administration (10 days) in growing Sprague-Dawley rats, WAY-161503 decreased food intake and attenuated body weight gain. Finally, following chronic administration (15 days) of WAY-161503 to obese Zuker rats, the rats maintained a 30% decrease in food intake over the 15-day period combined with a 25 g decrease in body weight relative to vehicle-treated controls demonstrating a lack of tolerance to its anorectic effects.
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PMID:Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503. 1643 Aug 74

The serotonin (5-hydroxytryptamine) 5-HT2 receptor subfamily consists of three members, 5-HT2A, 5-HT2B, and 5-HT2C. These receptors share high homology in their amino acid sequence, have similar signaling pathways, and have been indicated to play important roles in feeding, anxiety, aggression, sexual behavior, mood, and pain. Subtype-selective agonists and antagonists have been explored as drugs for hypertension, Parkinson's disease, sleep disorders, anxiety, depression, schizophrenia, and obesity. In this study, we report the development of homogeneous agonist binding assays in a scintillation proximity assay (SPA) format to determine the high-affinity binding state of agonist compounds for the human 5-HT2C, 5-HT2A, and 5-HT2B receptors. The 5-HT2 agonist 1-(4- [125I]iodo-2,5-dimethoxyphenyl)-2-aminopropane ([125I]DOI) was used to label the high-affinity sites for the 5-HT2A and 5-HT2C receptors. The high-affinity sites for the 5-HT2B receptor were labeled with [3H]lysergic acid diethylamide. Total receptor expression was determined with the 5-HT2 antagonist [3H]mesulergine for the 5-HT2B and 5-HT2C receptors, and [3H]ketanserin for the 5-HT2A receptor. The agonist high-affinity binding sites accounted for 2.3% (5-HT(2C) receptor), 4.0% (5-HT2A receptor), and 22% (5-HT2B receptor) of the total receptor population. Competition binding studies using known agonists indicated high Z' values of the agonist binding assays in SPA format (Z' > 0.70). The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays. These results indicate that agonist binding assays in SPA format can be easily adapted to a high throughput assay to screen for selective 5-HT2C receptor agonists, as well as for selectivity profiling of the compounds.
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PMID:Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes. 1643 60

Serotonin has been related to feeding behaviour and body weight control through its suppressive effect on appetite. Conflicting results have been published in the literature regarding the association between the - 1438 G/A promoter polymorphism of the 5HT2A gene with obesity-related variables. The aim of this study was to assess the association between the--1438 G/A polymorphism of the 5HT2A gene with childhood obesity in a Spanish population. A total of 136 cases aged 6-16 years with BMI above the 97th percentile of the Spanish BMI reference data for age and gender were matched by gender and age (+/- 6 months) with 136 controls. Additionally, 43 obese children and their parents were selected for a family-based association study (case-parent study). Genotyping was carried out by polymerase chain reaction and restriction enzyme analysis. Conditional logistic regression and transmission/disequilibrium test were used to assess genotype-obesity association. In the matched case-control study, the crude and adjusted odds ratios for the association between 5HT2A--1438 G/A genotypes were nonsignificant. Likewise, no association is suggested by the case-parent study. In conclusion, it is unlikely that the--1438 G/A polymorphism of 5HT2A gene may influence obesity in a Spanish children population.
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PMID:No evidence of association between the serotonin 2A receptor--1438G/A promoter polymorphism and childhood obesity in a Spanish population: A case-parent study and a matched case-control study. 1649 45

The physicochemical properties of 1-benzenesulfonyl-4-(piperazin-1-yl)-indole hydrochloride, a novel 5-HT(6) receptor antagonist for the treatment of obesity were characterized. Two solid state forms were identified at ambient conditions (23 degrees C): an anhydrate form (1) and a hydrate form (2), with 1.5 moles of H(2)O. The latter easily dehydrates and rehydrates without affecting the crystal morphology. Investigations of the propensity for interconversion between the two forms reveal that a) conversion of 2-->1 takes place above 145 degrees C and that b) conversion of 1-->2 only occurs after crystallization from supersaturated aqueous solutions at a water activity >or=0.94 or in the presence of comparable amounts of crystals of 2 in water at ambient conditions. However, in an equimolar suspension of 1 and 2 at 37 degrees C no phase transformation was observed. Thus, the difference in chemical potential between the two forms is small. Form 1 was shown to have overall favorable solid state properties and, hence, considered the preferred form for continued pharmaceutical development. The characterization was performed by means of light microscopy, scanning electron microscopy, powder X-ray diffraction, FTIR/NIR-spectroscopy, differential scanning calorimetry, hot stage microscopy, thermogravimetry, dynamic vapor sorption, Karl Fischer water content determination, phase stability studies of suspensions, solubility, and intrinsic dissolution rate measurements.
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PMID:Physical characterization of anhydrous and hydrous forms of the hydrochloride salt of BVT.5182 a novel 5-HT(6) receptor antagonist. 1653 99

Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research interest has advanced the understanding of the functional roles and the pharmacophore requirements of this receptor. Two 5-HT(6) receptor antagonists have already entered Phase II clinical trials for the enhancement of cognitive function. Since the first discovery of selective ligands for the 5-HT(6) receptor by HTS in 1998, several medicinal-chemistry-driven approaches have delivered highly selective lead structures with well-defined functionalities, starting from either the endogenous ligand 5-HT or the chemical structures identified by HTS. The concept of 'scaffold hopping' has been employed to expand the variability of the available chemical scaffolds and to generate patentable ligands. Supported by pharmacophore models, which have been established recently, the binding and functionality (structure-activity relationships) of the lead structures have been optimized further.
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PMID:Medicinal chemistry strategies to 5-HT(6) receptor ligands as potential cognitive enhancers and antiobesity agents. 1658 Sep 70

Central biogenic amine systems have long been studied for their effects on feeding behavior, energy balance, and maintenance of body weight. Those monoaminergic systems that use dopamine (DA), norepinephrine (NE), and serotonin (5-hydroxytryptamine, 5-HT) as neurotransmitters have been the main targets of study. A number of antiobesity medications that affect monoaminergic activity have appeared on the market and/or in clinical trials. Early examples of such agents are the so-called CNS stimulants, e.g., the amphetamines, phentermine, ephedrine, etc. These agents release monoamines from neuronal stores, and their antiobesity activity seems to be tied most closely to their ability to release NE. Inhibitors of neuronal reuptake of NE or 5-HT have been shown to reduce feeding and weight gain both preclinically and clinically. However, the magnitude and sustainability of such effects in clinical trials has generally not been great enough to register or label these agents for the treatment of obesity. Sibutramine, however, is an exception. This compound is metabolized in vivo to produce metabolites that have varying degrees of inhibition of NE, 5-HT, and/or DA uptake. Sibutramine is the only drug affecting monoaminergic systems currently approved for the long-term control of obesity. Research continues on serotonergic and histaminergic systems to determine if targets such as the 5-HT2C and H3 receptors may be suitable for developing antiobesity agents. Because the clinical antiobesity effects of monoaminergic drugs have been modest, future directions include looking at combinations of different monoaminergic mechanisms and/or combinations of monoaminergic drugs with non-monoaminergic mechanisms.
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PMID:Central nervous system biogenic amine targets for control of appetite and energy expenditure. 1662 92

E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator. Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control. Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain. These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.
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PMID:Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats. 1678 8

We evaluate the likely utility of drugs that interact, either directly or indirectly, with monoamine binding receptors for the treatment of obesity. We discuss ligands at dopaminergic, adrenergic, serotoninergic and histaminergic receptors and also drugs that either release or inhibit the reuptake of monoamine neurotransmitters. We review evidence from preclinical studies of receptor distribution and function, together with the consequences of gene deletion in transgenic mouse strains and the results from human studies where these are available. In addition we consider the side effect profiles that would be expected of these potential anti-obesity treatments. We conclude that compounds interacting with 5-HT(2C), 5-HT(6) and histamine H(3) receptors may be of particular interest as specific drug development targets for the treatment of appetite disturbance in obesity.
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PMID:Monoamine receptors in the regulation of feeding behaviour and energy balance. 1678 30

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