RESUMEN
AIM: These studies were performed to test the hypothesis that endogenous neuropeptide Y (NPY) acting on the NPY Y(5) receptor subtype contributes to the control of food intake. The hypothesis was tested using S 25585-a newly synthesized NPY Y(5) receptor antagonist. METHODS AND RESULTS: S 25585 was shown to be a high-affinity antagonist of the NPY Y(5) receptor subtype (IC(50) 5 nM) with no significant affinity toward other NPY receptor subtypes and over 40 other receptors, channels or uptake systems. S 25585 (7.5 mg/kg, i.p.) did not induce a conditioned taste aversion, significantly alter need-induced sodium appetite or induce pica, suggesting that at this dose the compound did not induce illness or malaise. In satiated rats, S 25585 (5.0 and 7.5 mg/kg, i.p.) significantly decreased the overfeeding induced by i.c.v. injection of NPY (1 microg) and the highly selective NPY Y(5) receptor agonist [hPP(1-17), Ala(31), Aib(32)]NPY (0.7 microg). In rats fasted for 4 h immediately before the dark phase, analysis of the microstructure of feeding behavior revealed that S 25585 significantly increased latency to eat and significantly decreased the duration and size of the meals without altering the meal number or eating rate. Analysis of the behavioral satiety sequence at this time revealed that the animals passed through the normal pattern of feeding, grooming and resting. Although S 25585 appeared to be influencing a physiological system controlling appetite, this does not involve the NPY Y(5) receptor since the antagonist also markedly reduced food intake in the NPY Y(5) knockout mouse. CONCLUSIONS: The results presented do not support a role for the NPY Y(5) receptor in the control of food intake. The results further illustrate that it is imperative that the activity of any new NPY Y(5) antagonist be assessed in the NPY Y(5) knockout mouse before assuming that its effect on food intake is due to blockade of this receptor.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Apetito/fisiología , Condicionamiento Psicológico/fisiología , Masculino , Ratones , Ratones Noqueados , Pica/fisiopatología , Ratas , Ratas Long-Evans , Ratas Wistar , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/fisiología , Respuesta de Saciedad/fisiología , Cloruro de Sodio Dietético/administración & dosificación , Gusto/fisiologíaRESUMEN
AIM: Although melanin-concentrating hormone (MCH) is believed to be an important regulator of feeding behavior, both its acute and chronic effects on food intake as well as its interaction with other brain peptides involved in the control of appetite remain unclear. Therefore, the acute effects of MCH on food intake and the chronic effect of MCH on food intake and the gene expression of various hypothalamic peptides involved in the control of appetite were studied in rats. METHODS AND RESULTS: Either the acute or the continuous intraventricular infusion of MCH for 12 days stimulated feeding in both Wistar or Sprague-Dawley rats. Removal of the hypothalamus at the end of the chronic infusion studies allowed measurement of the expression of mRNAs encoding for MCH, neuropeptide Y (NPY), orexin, agouti gene-related peptide, cocaine and amphetamine-related transcript and neurotensin-neuropeptides involved in the control of appetite. Chronic intraventricular infusion of MCH activated only NPY mRNA synthesis in Sprague-Dawley rats. The increase in food intake in response to MCH in Sprague-Dawley rats did not appear to be due to the release of NPY since combination studies demonstrated consistently additive effects of the two peptides on food intake at maximum or near maximum doses. CONCLUSIONS: These results strongly suggest that MCH is an orexigenic peptide involved in the control of both short- and long term food intake in satiated rats and further indicate that the MCH pathway is a possible target for the control of food intake and obesity.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Hormonas Hipotalámicas/farmacología , Péptidos y Proteínas de Señalización Intracelular , Melaninas/farmacología , Neuropéptido Y/genética , Hormonas Hipofisarias/farmacología , Proteína Relacionada con Agouti , Animales , Peso Corporal , Proteínas Portadoras/genética , Cartilla de ADN , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Regulación de la Expresión Génica , Hormonas Hipotalámicas/administración & dosificación , Hormonas Hipotalámicas/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Masculino , Melaninas/administración & dosificación , Melaninas/metabolismo , Proteínas del Tejido Nervioso/genética , Neuropéptidos/genética , Neurotensina/genética , Orexinas , Hormonas Hipofisarias/administración & dosificación , Hormonas Hipofisarias/metabolismo , Reacción en Cadena de la Polimerasa , Proteínas/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
AIM: The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y(1) receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y2 and NPY Y5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.
Asunto(s)
Depresores del Apetito , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Anticuerpos/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Diseño de Fármacos , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético , Humanos , Ratones , Ratones Noqueados , Naftalenos/farmacología , Neuropéptido Y/antagonistas & inhibidores , Neuropéptido Y/genética , Neuropéptido Y/inmunología , Neuropéptido Y/farmacología , Oligodesoxirribonucleótidos Antisentido/farmacología , Pirimidinas/farmacología , Receptores de Neuropéptido Y/deficiencia , Receptores de Neuropéptido Y/metabolismoRESUMEN
Several studies have shown that melanin-concentrating hormone (MCH) is an orexigenic peptide in rat. In the present study, a structure-activity relationship with MCH analogs was performed in rat, both in vitro and in vivo. On rat recombinant SLC-1 receptor, both cAMP inhibition and [(125)I]S36057 binding were measured. In vivo, these analogs were injected intracerebroventricularly in rats and their effects were evaluated upon food intake. First, data obtained with the rat recombinant receptor were highly correlated with those obtained from its human counterpart. Second, agonist potencies in the cAMP assay were also highly correlated with binding affinities. These peptides could be classified into several groups according to their potency at the SLC-1 receptor (from subnanomolar activity to complete inactivity). Indeed, there was a strong correlation between their effects upon food intake and the results obtained at the rat SLC-1 receptor. The present report describes for the first time the rat SLC-1 receptor pharmacology and clearly establishes the relevance of the SLC-1 receptor in feeding behavior.
Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Hormonas Hipotalámicas/farmacología , Melaninas/farmacología , Hormonas Hipofisarias/farmacología , Receptores de Somatostatina/efectos de los fármacos , Animales , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Clonación Molecular , AMP Cíclico/metabolismo , Inyecciones Intraventriculares , Masculino , Oligopéptidos/farmacología , Poli A/metabolismo , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
INTRODUCTION: The purpose of this study was to test the continuing validity of the hypothesis that neuropeptide Y (NPY) produced in the brain controls food intake through an interaction with the NPY Y(5) receptor subtype. METHODS: The hypothesis was tested using CGP 71683A a potent and highly selective non-peptide antagonist of the NPY Y(5) receptor which was administered into the right lateral ventricle of obese Zucker fa/fa rats. RESULTS: Intraventricular injection of 3.4 nmol/kg NPY increased food intake during a 2 h test period. Doses of CGP 71683A in excess of 15 nmol/kg (i.cv.) resulted in blockade of the increase in food intake produced by NPY. Repeated daily injection of CGP 71683A (30--300 nmol/kg, i.cv.) immediately before the dark phase produced a dose-dependent and slowly developing decrease in food intake. CGP 71683A has a low affinity for NPY Y(1), Y(2) and Y(4) receptors but a very high affinity for the NPY Y(5) receptor (Ki, 1.4 nM). Surprisingly, CGP 71683A had similarly high affinity for muscarinic receptors (Ki, 2.7 nM) and for the serotonin uptake recognition site (Ki, 6.2 nM) in rat brain. Anatomic analysis of the brain after treatment with CGP 71683A demonstrated an inflammatory response associated with the fall in food intake. CONCLUSIONS: While the fall in food intake in response to CGP 71683A may have a Y(5) component, interactions with other receptors or inflammatory mediators may also play a role. It is concluded that CGP 71683A is an imprecise tool for investigating the role of the NPY Y(5) receptor in the control of physiological processes including food intake. International Journal of Obesity (2001) 25, 84-94
Asunto(s)
Ingestión de Alimentos/fisiología , Ingestión de Energía/efectos de los fármacos , Naftalenos/farmacología , Neuropéptido Y/metabolismo , Pirimidinas/farmacología , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Encefalitis , Ingestión de Energía/genética , Inyecciones Intraventriculares , Masculino , Naftalenos/administración & dosificación , Obesidad/metabolismo , Pirimidinas/administración & dosificación , Ratas , Ratas Wistar , Ratas Zucker , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Factores de TiempoRESUMEN
Neuropeptide Y (NPY), one of the most abundant peptides in rat and human brains, appears to act in the hypothalamus to stimulate feeding. It was first suggested that the NPY Y1 receptor (Y1R) was involved in feeding stimulated by NPY. More recently a novel NPY receptor subtype (Y5R) was identified in rat and human as the NPY feeding receptor subtype. There is, however, no absolute consensus since selective Y1R antagonists also antagonize NPY-induced hyperphagia. Nevertheless, new anti-obesity drugs may emerge from further pharmacological characterization of the NPY receptors and their antagonists. A large panel of Y1R and Y5R antagonists (such as CGP71683A, BIBO3304, BIBP3226, 1229U91, and SYNAPTIC and BANYU derivatives but also patentable in-house-synthesized compounds) have been evaluated through in vitro and in vivo tests in an attempt to establish a predictive relationship between the binding selectivity for human receptors, the potency in isolated organs assays, and the inhibitory effect on food intake in both normal and obese hyperphagic rodents. Although these results do not allow one to conclude on the implication of a single receptor subtype at the molecular level, this approach is crucial for the design of novel NPY receptor antagonists with potential use as anti-obesity drugs and for evaluation of their possible adverse peripheral side effects, such as hypotension.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Receptores de Neuropéptido Y/fisiología , Animales , Arginina/análogos & derivados , Arginina/metabolismo , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Células CHO , Células COS , Cricetinae , Femenino , Humanos , Masculino , Ratones , Ratones Obesos , Naftalenos/farmacología , Pirimidinas/farmacología , Conejos , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Obesity affects a large population of industrialised countries in which occurrence may reach 20%. The multifactorial aspect of the pathology prompted us to develop new entities associating favourable effects on both eating behaviour and metabolic parameters. The 2-trifluoromethyl-benzocyloheptene moiety has been combined with an imidazoline ring for synthesising a new anti-obesity agent. Preparation of the already known 2-trifluoromethyl-5-H-6,7,8,9-tetrahydro-benzocyclohepten-7-one as a key intermediate has been significantly improved, and an enantioselective procedure has been developed for imidazoline construction. The syntheses and pharmacological profiles of the compounds are presented here, particularly the effects on eating behaviour and body weight, and the putative involvement of the L-enantiomer in the treatment of metabolic diseases.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Animales , Fármacos Antiobesidad/farmacología , Depresores del Apetito/síntesis química , Depresores del Apetito/farmacología , Monoaminas Biogénicas/metabolismo , Presión Sanguínea/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Fluorobencenos/síntesis química , Fluorobencenos/farmacología , Técnicas In Vitro , Masculino , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Ratas Zucker , Receptores de Droga/efectos de los fármacos , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , EstereoisomerismoRESUMEN
The new compound S 15261 (CAS 159978-02-6) is the I-isomer of 3-[2-[2-[4-[2-(alpha-Fluorenylacetylamino)ethyl]benzoyloxy]ethylam ino]-1- methoxyethyl]trifluoromethylbenzene. The general synthetic pathway used for the preparation of S 15261 and related esters is given in this paper. This compound was selected for its promising therapeutical action on blood glucose, insulin resistance and associated risk factors present in patients with non-insulin-dependent Diabetes mellitus (NIDDM). The general pharmacological profile of S 15261 was investigated. The data given in this paper show that S 15261 has presented a very low acute toxicity (lethal dose in mice greater than 1600 mg/kg orally) and did not induce significant behavioural changes in rats. A poor anorectic effects was observed after acute administration in rats. In guinea pigs S 15261 acutely induced a significant and dose-dependent hypoglycaemic effect (ED25 = 40 mg/kg orally). Biogenic amines and their metabolites in different structures of the brain were only slightly affected after acute administration of S 15261. Chronic administration of this compound (2.5 mg/kg bid for 14 days p.o.) did not cause significant alterations in the brain amines content, with the exception of an increase of serotonin (19%) in the striatum, a result not confirmed by the dose-effect study (from 1 mg/kg to 12.5 mg/kg bid for 14 days p.o.). In vitro binding assays with 31 different receptors did not show significant affinity of S 15261 for any of them. The rat arterial blood pressure was decreased (12 mmHg) after acute (25 mg/kg i.v.) or repeated administration (2.5 mg/kg bid for 14 days p.o.) without any dose-dependent effect. We therefore conclude that S 15261 may not have significant adverse effect even at doses higher than the pharmacological effective range of doses. Although the mechanism of action of this new class of compounds was not fully understood, other pharmacological data suggest that S 15261 acts at both the liver (intraportal infusion) and skeletal muscle (microdialysis studies) at least in part to enhance insulin sensitivity. For all these activities S 15261 may be useful to treat patients with NIDDM or insulin resistance known to be the major risk for onset of NIDDM.
Asunto(s)
Fluorenos/farmacología , Resistencia a la Insulina/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/antagonistas & inhibidores , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Monoaminas Biogénicas/metabolismo , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Fluorenos/farmacocinética , Fluorenos/toxicidad , Cobayas , Masculino , Ratones , Dimensión del Dolor/efectos de los fármacos , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Superficie Celular/metabolismo , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
A new oral agent, S15261 (the L-isomer of 3-[2-[2-[4-[2-[alpha-fluorenyl acetyl amino ethyl] benzoyloxy] ethyl amino] 1-methoxy ethyl] trifluoromethyl-benzene), has been developed for the treatment of the so-called "insulin resistance syndrome". In obese, insulin-resistant ageing Sprague-Dawley rats, chronic treatment with S15261 (0.5-2.5 mg.kg-1.day-1 twice per day, for 14 days) resulted in dose-dependent decreases in plasma insulin (43%), and triglyceride levels (36%), and in an increase of the glucose disposal rate during an intravenous glucose tolerance test (IVGTT) (48.5%). An increase in peripheral insulin sensitivity produced by S15261 was revealed by the glucose clamp technique. Thus, the glucose infusion rate was increased by 20% whilst steady-state insulin levels decreased by 15%. At the higher doses S15261 led to a decrease in body weight (3%), plasma glucose (13%) and blood pressure (8 mm Hg) in mildly hypertensive animals. At the doses used to achieve these results, the compound has no hypoglycaemic activity in normoglycaemic animals. Acute administration of S15261 directly into the portal vein provoked a marked increase in glucose disappearance rate during an intravenous glucose tolerance test (60%) and also in the pancreatic response to the glucose challenge. Thus, acute administration of the compound has a direct effect on glucose metabolism. These data suggest that S15261 could be a useful agent for the treatment of the insulin resistance syndrome.
Asunto(s)
Fluorenos , Fluorobencenos/farmacología , Resistencia a la Insulina/fisiología , Animales , Glucemia/análisis , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Colesterol/sangre , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Fluorobencenos/administración & dosificación , Fluorobencenos/uso terapéutico , Glucosa/metabolismo , Glucosa/farmacología , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Técnicas In Vitro , Infusiones Intravenosas , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Glucógeno Hepático/metabolismo , Masculino , Obesidad/fisiopatología , Vena Porta , Ratas , Ratas Sprague-Dawley , Síndrome , Triglicéridos/sangreRESUMEN
Biogenic amines in pons and striatum have been dosed in twenty-four months old Wistar male rats. Choline acetyltransferase (CAT) and acetylcholine esterase (ACHesterase) activities, [3H] choline uptake by a synaptosomal preparation, [3H] quinuclidinyl benzylate (QNB) binding to muscarinic cholinergic receptors have been determined in hippocampus. Malondialdehyde (MDA) levels in plasma, in liver and in lungs and the characteristics of the skin collagen have been evaluated. Important differences are shown in comparison with three months old of the same strain animals.