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)

Benzazepines 1 and 2 (SCH 23390 and SCH 39166, respectively) are two classical benzazepine D1/D5 antagonists, with Ki values 1.4 and 1.2 nM, respectively. Compound 2 has been in human clinical trials for a variety of diseases, including schizophrenia, cocaine addition, and obesity. Both 1 and 2 displayed low plasma levels and poor oral bioavailability, due to rapid first-pass metabolism of the phenol moieties. Several heterocyclic systems containing an N-H hydrogen bond donor were synthesized and evaluated as phenol isosteres. The preference orientation of the hydrogen bond was established by comparison of analogues containing different NH vectors. Replacement of the phenol group of 2 with an indole ring generated the first potent D1/D5 antagonist 11b. Further optimization led to the synthesis of very potent benzimidazolones 19, 20 and benzothiazolone analogues 28, 29. These compounds have excellent selectivity over D2-D4 receptors, alpha2a receptor, and the 5-HT transporter. Compared to 2, these heterocyclic phenol isosteres showed much better pharmacokinetic profiles as demonstrated by rat plasma levels. In sharp contrast, similar phenolic replacements in 1 decreased the binding affinity dramatically, presumably due to a conformational change of the pendant phenyl group. However, one indazole compound 33 was identified as a potent D1/D5 ligand in this series.
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PMID:Dopamine D1/D5 receptor antagonists with improved pharmacokinetics: design, synthesis, and biological evaluation of phenol bioisosteric analogues of benzazepine D1/D5 antagonists. 1568 53

The pharmacological profile of WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine (HT)(2C) (serotonin) receptor-selective agonist is presented. WAY-163909 displaced [(125)I]2,5-dimethoxy-4-iodoamphetamine binding from human 5-HT(2C) receptor sites, in Chinese hamster ovary (CHO) cell membranes, with a K(i) value of 10.5 +/- 1.1 nM. Binding affinities determined for the human 5-HT(2A) and 5-HT(2B) receptor subtypes were 212 and 485 nM, respectively. In functional studies, WAY-163909 stimulated the mobilization of intracellular calcium in CHO cells stably expressing the human 5-HT(2C) receptor with an EC(50) value of 8 nM, and E(max) relative to 5-HT of 90%. WAY-163909 failed to stimulate calcium mobilization in cells expressing the human 5-HT(2A) receptor subtype (EC(50) >> 10muM) and was a 5-HT(2B) receptor partial agonist (EC(50) 185 nM, E(max) 40%). WAY-163909 exhibited negligible affinity (<50% inhibition at 1 muM) for other receptor sites examined, including human 5-HT(1A), D2, and D3 receptors, and the 5-HT transporter binding site in rat cortical membranes. WAY-163909 exhibited weak affinity for the human D4 (245 nM) and 5-HT(7) (343 nM) receptor subtypes and the alpha1 binding site in rat cortical membranes (665 nM). WAY-163909 produced a dose-dependent reduction in food intake in normal Sprague-Dawley rats (ED(50) = 2.93 mg/kg), an effect blocked by a 5-HT(2C) receptor antagonist but not by a 5-HT(2A) or 5-HT(2B) receptor antagonist. In addition, WAY-163909 decreased food intake in obese Zucker rats and diet-induced obese mice with ED(50) values of 1.4 and 5.19 mg/kg i.p., respectively, consistent with the potential utility of 5-HT(2C) receptor agonists as anti-obesity agents.
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PMID:WAY-163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole], a novel 5-hydroxytryptamine 2C receptor-selective agonist with anorectic activity. 1570 38

Obesity is increasing in severity and prevalence in the United States and represents a major public health issue. No effective pharmacologic treatment leading to sustained weight loss currently exists. The growing interest in the regulation of food intake stems from the current drug treatments for obesity, almost all of which interfere with the monoamine system. Our knowledge of potential interactions between the orexigenic and anorexigenic pathways is limited and fragmented, making the development of targeted drug therapy for obesity difficult. The present review of the interaction of neuropeptides and monoamines emphasizes the complexity of the central mechanisms that regulate feeding behavior. Two main systems are implicated in food intake regulation: neuropeptide Y (NPY) and pro-opiomelanocortin. alpha-Melanocyte-stimulating hormone is a tridecapeptide cleaved from pro-opiomelanocortin that acts to inhibit food intake. The predominant NPY orexigenic receptors are NPY-Y1 and NPY-Y5, and the two anorexigenic melanocortin receptors involved in hypothalamic food intake control are MC3-R and MC4-R. Both neuropeptides interact with monoamines in the hypothalamus to control physiologic states such as hunger, satiation, and satiety. Serotonin suppresses food intake and body weight, acting mainly through the serotonin 1B receptor. Dopamine regulates hunger and satiety by acting in specific hypothalamic areas, through the D1 and D2 receptors. Noradrenaline activation of alpha1- and beta2-adrenoceptors decreases food intake, and stimulation of the alpha2-adrenoceptor increases food intake. A better understanding of the detailed mechanisms underlying the pathogenesis of hyperphagia and hypophagia is needed to develop new therapeutic approaches to obesity.
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PMID:Neuropeptide Y, alpha-melanocyte-stimulating hormone, and monoamines in food intake regulation. 1572 58

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selective 5-HT(6) ligands. Many of the compounds described in this paper possess excellent affinities, displaying pK(i) values greater than 8 (some even >9) and high selectivities against a wide range (>50) of other CNS relevant receptors. First, structure-affinity relationships of these ligands are discussed. In terms of functionality, high-affinity antagonists, as well as agonists and even partial agonists, were prepared. Compounds 19c and 19g represent the highest-affinity 5-HT(6) agonists ever reported in the literature. These valuable tool compounds should allow for the detailed study of the role of the 5-HT(6) receptor in relevant animal models of disorders such as cognition deficits, depression, anxiety, or obesity.
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PMID:Medicinal chemistry driven approaches toward novel and selective serotonin 5-HT6 receptor ligands. 1577 24

Diethylpropion (1-phenyl-2-diethylamine-1-propanone hydrochloride) is a stimulant drug with reinforcing properties that is used to treat obesity in humans. While the anorectic properties of diethylpropion are mediated by a noradrenergic mechanism, stimulant properties depend on its effects on the serotonergic (5-HT) and/or dopaminergic systems. In this study we investigated the role of the 5-HT1A-receptor in the acute behavioral effects of diethylpropion in marmosets (Callithrix penicillata). Animals were pretreated with the selective 5-HT1A-receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide trihydrochloride (WAY 100635; 0.2, 0.4, 0.8 mg/kg, i.p.) or saline (i.p.) and received a treatment with diethylpropion (10 mg/kg, i.p) or saline (i.p.). Diethylpropion induced an increase in locomotor activity in 60% of the monkeys, which were classified as diethylpropion sensitive, but did not affect locomotion in 40% of the monkeys (diethylpropion insensitive). Sensitivity analysis revealed two types of responders to diethylpropion. In the sensitive animals (type A) diethylpropion increased locomotor activity and anxiogenic-like behavior, but decreased bodycare activities. In the insensitive animals (type B) diethylpropion did not affect locomotor and bodycare activity after diethylpropion, but led to a strong increase in anxiogenic-like behavioral responses. Selective 5-HT1A-receptor antagonism modulated the acute diethylpropion effects responder type specifically. In the sensitive (type A) monkeys WAY 100635 blocked the diethylpropion-induced increase in locomotor activity, while not affecting anxiogenic-like behavioral responses or the suppression of bodycare activities. In the insensitive monkeys, WAY 100635 had no effect on locomotor activity after diethylpropion, but blocked diethylpropion effects on some anxiogenic-like behavioral responses. In conclusion, these results suggest an essential contribution of the 5-HT1A-receptor to the stimulant effects of diethylpropion, which is responder type specific. It also suggests the 5-HT1A-receptor to be a source of the interindividual variance in the acute behavioral response to the stimulant diethylpropion in monkeys.
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PMID:Serotonin1A-receptor antagonism blocks psychostimulant properties of diethylpropion in marmosets (Callithrix penicillata). 1577 78

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 Center for Business Intelligence (CBI) presented this 2-day conference as part of its business of discovery series. The meeting, which targeted senior level industry personnel, highlighted the latest developments in the search for effective and safe obesity drugs. The adverse health consequences and growing prevalence of obesity make this condition a major worldwide public health concern. Consistent with the multi-faceted nature of the body weight regulatory system, the presentations featured a variety of approaches aimed at different neuroendocrine and peripheral tissue targets. Clinical as well as basic data on agents in various stages of development were presented. These included rimonabant, an inhibitor of the endocannabinoid system, which has undergone extensive phase III clinical testing, and two selective 5-HT(2C) agonists, ATH-88651 (Athersys Inc) and APD-356 (Arena Pharmaceuticals Inc), which are in earlier stage development. Synthetic analogs of the gut and islet peptide hormones, PYY3-36 and amylin, which are in early-stage development as anorexigenic agents, were also discussed. More basic research-oriented presentations featured the potential therapeutic utility of melanocortin 4 receptor agonists and the inhibition of the gastric peptide ghrelin and the enzymes diacylglycerol acyltransferase 1 and 11beta-hydroxysteroid dehydrogenase 1. Another presentation addressed the problem of leptin resistance. A novel technology that measures extracellular flux rates and its application in screening obesity agents that target thermogenesis was also discussed.
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PMID:Obesity Drug Development Summit. 21-22 July, 2005, Arlington, VA, USA. 1611 85

Obesity continues to be a burgeoning health problem worldwide. Before their removal from the market, fenfluramine and the more active enantiomer dexfenfluramine were considered to be among the most effective of weight loss agents. Much of the weight loss produced by fenfluramine was attributed to the direct activation of serotonin 5-HT(2C) receptors in the central nervous system via the desmethyl-metabolite of fenfluramine, norfenfluramine. Norfenfluramine, however, is non-selective, activating additional serotonin receptors, such as 5-HT(2A) and 5-HT(2B), which likely mediated the heart valve hypertrophy seen in many patients. Development of highly selective 5-HT(2C) agonists may recapitulate the clinical anti-obesity properties observed with fenfluramine while avoiding the significant cardiovascular and pulmonary side effects.
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PMID:Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. 1624 24

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.
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PMID:Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists. 1625 7

Weight regulation is a complex system necessary for maintaining health. Obesity and cachexia are consequences of dysregulation and cause significant physical morbidity and mortality. In the developed world, obesity is a growing epidemic. A greater understanding of the neuroanatomy of weight regulation has been gained through advances in imaging and neural mapping techniques. The neural connections between key hypothalamic and other central nuclei have been elucidated. Advances in molecular biology have led to the identification and cloning of important peripheral and central weight regulating peptides. Weight gain as a consequence of antipsychotic use is increasingly being recognized as a serious clinical issue. The weight regulation system provides a framework upon which antipsychotics exert their weight-inducing effects. Some studies have sought, with inconsistent results, to establish associations between antipsychotic use and levels of weight regulating mediators. The receptor pharmacology of antipsychotics known to increase weight can be studied with a view to establishing genetic variants contributing to the risk. To date, the 5-HT(2C) receptor 759C/T polymorphism shows most promise. Further studies are required to replicate previous findings and establish new associations.
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PMID:An overview of the central control of weight regulation and the effect of antipsychotic medication. 1628 Mar 36


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