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)

It was first established in the 1970s that the brain serotonin (5-HT) system was involved in the control of eating. Subsequent progress in the molecular pharmacology of 5-HT receptors, and the development of selective 5-HT receptor ligands, has clarified our understanding of the role of 5-HT in the regulation of ingestive behavior. Of the 14 5-HT receptor subtypes currently described, 5-HT1A, 5-HT1B and 5-HT2C receptors have been of principal interest in the regulation of food intake. This is largely due to the development of suitable agonists, antagonists and gene-knockout animals with which the role of these receptors can be elucidated. The recent development of selective ligands and knockout mice for other 5-HT receptors, including the 5-HT2B and 5-HT6 receptors, has also suggested a role for these receptor subtypes in eating behavior. Studies using such approaches should further our understanding of the role of serotonin in the regulation of feeding behavior and thus, may lead to the development of novel, safe, serotonin receptor ligands for the treatment of obesity.
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PMID:Serotonin receptor ligands and the treatment of obesity. 1513 78

Serotonergic 5-HT2C and 5-HT1B receptors mediate inhibitory controls of eating. Questions have arisen about potential behavioral and neurological toxicity of drugs that stimulate the 2C site. We evaluated eating and other motor responses in male Dutch-belted rabbits after administration of m-chlorophenylpiperazine (mCPP). Studies conducted in vitro and in vivo assessed the pharmacological specificity of the ingestive actions of this agent. mCPP (0.15-10 micromol/kg sc) reduced consumption of chow and 20% sucrose solution with equal potencies (ED50 approximately equal 0.6 micromol/kg). In radioligand binding to rabbit cortex, mCPP displayed 15-fold higher affinity for 5-HT2C than for 5-HT1B receptors. The serotonin antagonist mesulergine (7000-fold selective for 5-HT2C) reversed the hypophagic action of mCPP, but the 5-HT1B/1D antagonist GR127,935 did not. GR127,935 (0.5 micromol/kg) did prevent hypophagia produced by the highly selective 5-HT1B/1D agonist GR46,611. Observational methods demonstrated that mCPP decreased the frequency of eating chow but increased other motor activities. When rabbits consumed sucrose, videoanalysis revealed that mCPP reduced total time licking and the duration of individual bouts, but not bout frequency or the actual rate of consumption. mCPP increased locomotor and other activities, and greatly increased vacuous oromotor stereotypies and tongue protrusions. Nonetheless, rabbits licked accurately at the spout for sucrose. When sucrose was infused intraorally through a cheek catheter, mCPP actually increased the peak amplitude and overall magnitude of jaw movements. We conclude that mCPP stimulates 5-HT2C receptors to reduce food intake in rabbits. This hypophagia involves disruption of appetitive components of eating and is accompanied by adverse motor actions. This profile raises questions about the use of the 5-HT2C receptor as a target for novel therapeutic agents for obesity.
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PMID:A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits. 1523 97

Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C, phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploiting pathway-selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.
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PMID:Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2. 1593 77

The occurrence of obesity, eating disorders, and related diseases has increased in many parts of the world. Given that few strong genetic factors have been found, it is clear that these are complex multi-factorial diseases. The serotonin receptor 2C, a member of the 5-HTergic system, has been implicated in the control of phagia and obesity. We report a detailed investigation of linkage disequilibrium (LD) within and between the HTR2C promoter and the flanking sequences around a commonly utilized marker in the second coding exon of HTR2C. We suggest that inconsistent associations between HTR2C and several phenotypes, including obesity, may be due to the LD pattern across the gene in which recombination and gene conversion have been influential. The nucleotide and haplotype distribution is consistent with that of the neutral mutation model. The number of haplotypes suggests demographic influences or over dominant selection that may have a function in HTR2C expression. Using the fine LD pattern, we describe a possible association with promoter haplotypes and diplotypes, including a GT microsatellite, and body mass index (BMI) > or =30 kgm(-2) (P<0.0001). SNP -995G>A heterozygotes, as well as promoter diplotypes, were found to marginally influence higher serum leptin corrected for percentage body fat (P=0.01), which might suggest that these subjects are leptin resistant. Our results complement previous studies of HTR2C in both mice and humans, and suggest the importance of genetic variation and elucidating the fine LD structure in uncovering the genetic factors of obesity.
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PMID:Complex HTR2C linkage disequilibrium and promoter associations with body mass index and serum leptin. 1602 72

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

Activation of central 5-HT2C receptors as a strategy for appetite suppression and weight control is supported by animal pharmacology and human clinical studies. Considerable evidence comes from the weight-loss effects of fenfluramine, a non-selective 5-HT2C agonist. Advances in molecular pharmacology have led to an understanding of the effects of 5-HT2C receptor activation on food intake and satiety, in addition to providing insight into the causes of cardiac valvular insufficiency and pulmonary hypertension associated with the use of fenfluramine. However, clinically validated animal models of drug-induced disease and knowledge of the molecular mechanisms of these safety issues is lacking. For this reason, the development of selective 5-HT2C agonists for the treatment of obesity has remained a challenge.
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PMID:The potential use of selective 5-HT2C agonists in treating obesity. 1650 63

The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.
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PMID:The identification of pyrimidine-diazabicyclo[3.3.0]octane derivatives as 5-HT2C receptor agonists. 1654 79

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

5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.
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PMID:The design and synthesis of a tricyclic single-nitrogen scaffold that serves as a 5-HT2C receptor agonist. 1675 Mar 64


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