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)

Fenfluramine (FE) is a halogenated amphetamine derivative used in the treatment of obesity and thought to induce serotonin (5-HT) release from nerve terminals and to reduce re-uptake. However, other pathways may also be involved. In this work, the effects of FE on the major striatal afferent systems, and the possible interactions of these systems in FE-induced striatal expression of Fos, were studied by lesion of the serotonergic and/or dopaminergic system and administration of NMDA glutamate (MK-801) or D1 dopamine (SCH-23390) receptor antagonists. Both the D1 and NMDA receptor antagonists suppressed Fos expression in response to FE almost entirely. FE-induced Fos expression was also dramatically reduced 24 h after 6-hydroxydopamine (6-OHDA) lesion of the dopaminergic system. However, the reduction was not so marked after chronic 6-OHDA lesion, probably due to compensatory changes. Chronic (5,7-dihydroxytryptamine injection, 4 weeks before) or acute (p-chlorophenylalanine injection) lesion of the serotonergic system led to a marked reduction in Fos expression in response to FE (decrease of about 50%). After simultaneous chronic lesion of both serotonergic and dopaminergic systems, a considerable number of Fos-positive nuclei were still observed (decrease of about 70% in the dorsal and dorsomedial regions). The FE-induced expression of Fos was almost totally suppressed (decrease of about 95% in the dorsal and dorsomedial regions) after simultaneous acute lesion. Our results indicate that FE-induced striatal expression of Fos is due in large measure to DA release and dopaminergic stimulation of D1 receptors. However, concurrent stimulation of NMDA glutamate receptors also appears to be essential, and 5-HT release (although not indispensable) doubles striatal Fos expression.
 ...
PMID:Interaction between the serotonergic, dopaminergic, and glutamatergic systems in fenfluramine-induced Fos expression in striatal neurons. 941 20

Anitobesity drugs must increase the sensitivity of the hypothalamic satiety center towards leptin and antagonize the synthesis and action of NPY. The array of pharmacologic tools available is vast and presently ineffective. Among peptide analogs considered for evaluation [NPY-5 antagonists and CCK-A, bombesin, amylin and melanocyte-stimulating hormone-4 (or melanin-concentrating hormone?) agonists], is there a place for GLP-1 and PACAP? GLP-1 receptors present in ARC, PVN, VMN, and SON are the target for both central and blood-borne GLP-1 in those hypothalamic neurons endowed with GLUT-2 and glucokinase. GLP-1, hypersecreted by L-cells after a meal, is a potent insulinotropic agent and, together with glucose, reduces food intake and induces c-fos in the ARC. PACAP is present in the ARC, PVN, and SCH, and its hypothalamic type I receptor elevates cAMP and inositol triphosphate in the PVN, where it may perhaps antagonize NPY-induced food intake and hyperinsulinemia. However, irrelevant neuroendocrine, autonomic, and circadian functions are also activated by this peptide, making it a less than ideal base on which to build an obesity treatment.
 ...
PMID:Is there appetite after GLP-1 and PACAP? 992 26

Some of the pathophysiological consequences of obesity include insulin resistance, increased renal sodium reabsorption, and the development of hypertension. Dopamine promotes renal sodium excretion via activation of D(1)-like receptors present on the proximal tubules. Reduced dopamine-induced natriuresis and a defect in D(1)-like receptor function have been reported in the proximal tubules of hypertensive animals. The present study investigated D(1)-like dopamine receptors and associated G proteins as the initial signaling components in the proximal tubular basolateral membranes of obese Zucker and control lean Zucker rats. We found that the obese rats were hyperinsulinemic, hyperglycemic, and hypertensive compared with the lean rats. Dopamine produced concentration-dependent inhibition of Na,K-ATPase activity in the proximal tubules of lean rats, whereas the inhibitory effect of dopamine was reduced in obese rats. The D(1)-like receptors measured by [(3)H]SCH 23390 binding revealed an approximately 45% decrease in B(max) without a change in K(d) in the basolateral membranes of obese rats compared with lean rats. Although we found an increase in G(q)/11alpha and no change in G(s)alpha in the basolateral membranes of obese rats, dopamine and SKF 38393 failed to stimulate G proteins as measured by [(35)S]GTPgammaS binding in obese rats, suggesting a receptor-G protein coupling defect. We conclude that decrease in D(1)-like dopamine receptor binding sites and diminished activation of G proteins, resulting perhaps from defective coupling, led to the reduced inhibition by dopamine of Na,K-ATPase activity in the proximal tubules of obese Zucker rats. Such a defect in renal dopamine receptor function may contribute to sodium retention and development of hypertension in obese rats.
 ...
PMID:Defective dopamine receptor function in proximal tubules of obese zucker rats. 1056 87

Fenfluramine (FE) is a halogenated amphetamine derivative that has been used in the treatment of obesity. It has been suggested that the effects of FE on the striatum are mediated by serotonergic mechanisms. However, several major afferent systems may be involved, and administration of FE may be useful to study interactions between these systems. In this work, the effects of FE on striatopallidal neurons and the possible involvement of the major striatal afferent systems were studied in rats by determination of FE-induced changes in striatal levels of preproenkephalin (PPE) mRNA using in situ hybridization. Injection of FE induced a significant increase (60%) in striatal levels of PPE mRNA. This increase was blocked by pretreatment with the D(1) dopamine receptor antagonist SCH-23390 or with the NMDA glutamate receptor antagonist MK-801, or by lesion of the serotonergic system with 5,7-dihydroxytryptamine or p-chlorophenylalanine. In 6-hydroxydopamine lesioned rats, the lesion-induced increase in PPE mRNA levels was not affected by injection of FE, but was reduced by simultaneous serotonergic deafferentation. The results suggest that the serotonergic, glutamatergic, and dopaminergic system interact to increase striatal PPE mRNA levels after FE administration.
 ...
PMID:Fenfluramine-induced increase in preproenkephalin mRNA levels in the striatum: interaction between the serotonergic, glutamatergic, and dopaminergic systems. 1065 25

The aim of this study was to examine the effects of different doses of typical antipsychotics, chlorpromazine (0.25-1 mg/kg) and haloperidol (0.25-1 mg/kg), and atypical antipsychotics, clozapine (0.5-2 mg/kg), olanzapine (0.25-1 mg/kg), risperidone (0.5-2 mg/kg), sulpiride (10-40 mg/kg) and dopamine D1 antagonist, SCH 23390 (0.25-1 mg/kg) on feeding behavior at different time intervals after acute administration. The study further investigated the central dopamine and serotonergic receptor involvement in clozapine-induced hyperphagia using SKF 38393, quinpirole and quipazine. Then, the authors also examined the effect of subchronic treatment for 21 days with fluoxetine on clozapine-induced hyperphagia and modulation of body weight and fat pad weights. The feeding behavior was assessed in nondeprived mice by presenting the palatable chow to different groups of mice in glass petri dishes and recording the food consumed at different time intervals. After acute administration, significant (P<.05) increase in food intake was observed at different time intervals with different doses of both typical and atypical antipsychotics. Further, clozapine-induced hyperphagia was significantly (P<.05) reversed after treatment with SKF 38393 (dopamine D1 agonist), quinpirole (dopamine D2 agonist) and quipazine (5-HT1B, 5-HT2 and 5-HT3 agonist). In subchronic study, treatment with fluoxetine (10 mg/kg) significantly (P<.05) antagonized the increase in body weight and food intake induced by clozapine (2 mg/kg). The current investigations underscore the reported increases in food intake and body weight gain observed with antipsychotics. The study further confirms the involvement of dopamine D1, D2 and serotonergic receptor involvement in clozapine-mediated hyperphagia. Further, the serotonergic agents may prove useful to counteract antipsychotic-induced obesity.
 ...
PMID:Studies on modulation of feeding behavior by atypical antipsychotics in female mice. 1181 4

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.
 ...
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

Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.
 ...
PMID:Effects of a selective melanin-concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet-induced obese mice. 1654 Jan 4

The anti-obesity effect of the serotonin and noradrenaline reuptake inhibitor sibutramine has been attributed to a dual mechanism involving a reduction of food intake and an increase in energy expenditure. This dual action increases the possibilities for induction of a negative energy balance, the principal goal of an anti-obesity treatment. To elucidate the mechanism behind sibutramine-induced increase in energy expenditure, we applied indirect calorimetry combined with monitoring locomotor activity and body temperature. We confirm that sibutramine has both anorectic and thermogenic effects. In addition, we show here that sibutramine also causes a dose-dependent increase in locomotor activity (LMA) of rats, occurring in parallel with increase in energy expenditure. The dose of sibutramine necessary to induce an effect on locomotion and energy expenditure was only marginally higher than the dose sufficient to induce a significant reduction of food intake. The relation between LMA and energy expenditure was similar to that found with d-amphetamine, which causes both hyper-locomotion and increased energy expenditure, but was different from 2,4-dinitrophenol which causes increase in energy expenditure but not in locomotion. The effect of sibutramine (20 mg/kg) on energy expenditure was not inhibited by the non-selective 5-HT receptor antagonist, metergoline (1 mg/kg), or a high dose (20 mg/kg) of the non-selective beta-blocker propranolol, but was blocked by D1 dopamine receptor inhibitor SCH 23390 (0.3 mg/kg). Therefore, we conclude that the effect of sibutramine on energy expenditure in rats is predominantly due to a dopamine-dependent increase in locomotor activity.
 ...
PMID:Locomotion is the major determinant of sibutramine-induced increase in energy expenditure. 1664 8

The brain regulates energy balance and spontaneous physical activity, including both small- and large-motor activities. Neural mediators of spontaneous physical activity are currently undefined, although the amount of time spent in sedentary positions versus standing and ambulating may be important in the energetics of human obesity. Orexin A, a neuropeptide produced in caudal hypothalamic areas and projecting throughout the neuraxis, enhances arousal and spontaneous physical activity. To test the hypothesis that orexin A affects the amount of time spent moving, we injected orexin A (0-1000 pmol) into three orexin projection sites in male Sprague-Dawley rats: hypothalamic paraventricular nucleus, rostral lateral hypothalamic area and substantia nigra pars compacta, and measured spontaneous physical activity. Orexin A affects local GABA release and we co-injected orexin A with a GABA agonist, muscimol, in each brain site. Dopamine signaling is important to substantia nigra function and so we also co-injected a dopamine 1 receptor antagonist (SCH 23390) in the substantia nigra pars compacta. In all brain sites orexin A significantly increased time spent vertical and ambulating. Muscimol significantly and dose-dependently inhibited orexin A effects on time spent moving only when administered to the rostral lateral hypothalamic area. In the substantia nigra pars compacta, SCH 23390 completely blocked orexin A-induced ambulation. These data indicate that orexin A influences time spent moving, in three brain sites utilizing separate signaling mechanisms. That orexin A modulation of spontaneous physical activity occurs in brain areas with multiple roles indicates generalization across brain site, and may reflect a fundamental mechanism for enhancing activity levels. This potential for conferring physical activity stimulation may be useful for inducing shifts in time spent moving, which has important implications for obesity.
 ...
PMID:Orexin A mediation of time spent moving in rats: neural mechanisms. 1680 7

The neuropeptide Y (NPY) Y(5) receptor is believed to be involved in the central regulation of appetite. Thus, antagonists of this receptor have been pursued as potential therapeutic agents for the treatment of obesity. A novel series of potent and selective phenylamide or biaryl urea NPY Y(5) receptor antagonists was identified. Four representative compounds from this series, SCH 208639 (N-[4-[(1,1-dimethylbutyl)thio]phenyl]-2,2-dimethylpropanamide), SCH 430765 (N-[[[3'-fluoro[1,1'-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), SCH 488106 (N-[[[3',5'-difluoro[1,1'-biphenyl]-4-yl]amino]carbonyl]-N-methyl-1-[(5-methyl-3-pyridinyl)carbonyl]-4-piperidinamine) and SCH 500946 (N-[[[5-(3,5-difluorophenyl)-2-pyrazinyl]amino]carbonyl]-N-methyl-1-(methylsulfonyl)-4-piperidinamine), behaved as competitive antagonists in radioligand binding assays, but displayed apparently insurmountable antagonism in a cell-based functional assay. The apparently insurmountable antagonism was due to slow receptor dissociation rates rather than covalent binding, because the antagonists' effects could be reduced by extensive washing of cells after antagonist exposure. A novel radioligand, [(35)S]SCH 500946, was also developed and used to characterize the interaction of these antagonists with the NPY Y(5) receptor. [(35)S]SCH 500946 had high affinity for the NPY Y(5) receptor (K(d)=0.29 nM), and the binding kinetics (k(on) 4.414 x 10(7) M(-)(1) min(-1); k(off) 0.009816 min(-1)) confirmed that the compound slowly dissociates from the receptor. In a competition binding assay, NPY failed to displace [(35)S]SCH 500946 completely, indicating that the binding sites for NPY and [(35)S]SCH 500946 are not identical. These data indicate that the apparent insurmountable antagonism of these NPY Y(5) receptor antagonists is attributable both to slow receptor dissociation rates and to binding at a site distinct from NPY.
 ...
PMID:Identification and characterization of pseudoirreversible nonpeptide antagonists of the neuropeptide Y Y5 receptor and development of a novel Y5-selective radioligand. 1897 48


1 2 3 Next >>