21 results on '"Della Zuana O"'
Search Results
2. Appetite suppression based on selective inhibition of NPY receptors
- Author
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Chamorro, S, Della-Zuana, O, Fauchère, J-L, Félétou, M, Galizzi, J-P, and Levens, N
- Published
- 2002
- Full Text
- View/download PDF
3. NPY Effects on Food Intake and Metabolism
- Author
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Levens, N. R., primary, Félétou, M., additional, Galizzi, J.-P, additional, Fauchére, J.-L., additional, Della-Zuana, O., additional, and Lonchampt, M., additional
- Published
- 2004
- Full Text
- View/download PDF
4. S15261, a new compound for the treatment of the insulin resistance syndrome
- Author
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Duhault, J., Lacour, F., Boulanger, M., Della-Zuana, O., Ravel, D., Wierzbicki, M., and Espinal, J.
- Published
- 1994
- Full Text
- View/download PDF
5. A potent and selective NPY Y5 antagonist reduces food intake but not through blockade of the NPY Y5 receptor
- Author
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Della-Zuana, O, Revereault, L, Beck-Sickinger, A, Monge, A, Caignard, D-H, Fauchère, J-L, Henlin, J-M, Audinot, V, Boutin, J A, Chamorro, S, Félétou, M, and Levens, N
- Published
- 2004
6. Appetite boosting property of pro-MCH131-165 (NEI-MCH) is associated with proteolytic resistance
- Author
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Maulon-Feraille, L., Della-Zuana, O., Suply, T., Rovère-Jovène, C., Audinot, V., Levens, N., Boutin, J.A., Duhault, J., Nahon, J.L., Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] - Published
- 2006
7. Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague-Dauwley rats
- Author
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Della-Zuana, O., Presse, F., Ortola, C., Duhault, J., Nahon, J.-L., Levens, N., Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Published
- 2002
8. ChemInform Abstract: General Pharmacology of S 15261 (I), a New Concept for Treatment of Diabetes.
- Author
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DUHAULT, J., primary, BERGER, S., additional, BOULANGER, M., additional, DELLA ZUANA, O., additional, LACOUR, F., additional, and WIERZBICKI, M., additional
- Published
- 1998
- Full Text
- View/download PDF
9. A potent and selective NPY Y5 antagonist reduces food intake but not through blockade of the NPY Y5 receptor.
- Author
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Della-Zuana, O., Revereault, L., Beck-Sickinger, A., Monge, A., Caignard, D.-H., Fauch&eagrave;re, J.-L., Henlin, J.-M., Audinot, V., Boutin, J.A., Chamorro, S., Félétou, M., and Levens, N.
- Subjects
- *
NEUROPEPTIDE Y , *CELL receptors , *INGESTION , *FOOD habits , *TASTE , *APPETITE , *PICA (Pathology) - Abstract
AIM:: These studies were performed to test the hypothesis that endogenous neuropeptide Y (NPY) acting on the NPY Y5 receptor subtype contributes to the control of food intake. The hypothesis was tested using S 25585-a newly synthesized NPY Y5 receptor antagonist. METHODS AND RESULTS:: S 25585 was shown to be a high-affinity antagonist of the NPY Y5 receptor subtype (IC50 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?µg) and the highly selective NPY Y5 receptor agonist [hPP1-17, Ala31, Aib32]NPY (0.7?µg). 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 Y5 receptor since the antagonist also markedly reduced food intake in the NPY Y5 knockout mouse. CONCLUSIONS:: The results presented do not support a role for the NPY Y5 receptor in the control of food intake. The results further illustrate that it is imperative that the activity of any new NPY Y5 antagonist be assessed in the NPY Y5 knockout mouse before assuming that its effect on food intake is due to blockade of this receptor.International Journal of Obesity (2004) 28, 628-639. doi:10.1038/sj.ijo.0802435 Published online 3 February 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
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10. [Interaction between environment and genetic background in type 2 diabetes: lessons from animal models].
- Author
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Bernard C, Della Zuana O, and Ktorza A
- Subjects
- Animals, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Type 2 epidemiology, Diet, Diet, High-Fat adverse effects, Disease Models, Animal, Energy Intake, Female, Fetal Growth Retardation etiology, France epidemiology, Genetic Predisposition to Disease, Humans, Infant, Newborn, Mice, Pregnancy, Prenatal Exposure Delayed Effects, Rats, Diabetes Mellitus, Type 2 genetics, Gene-Environment Interaction
- Abstract
The respective roles of predisposing genetic factors and environmental factors in the development of type 2 diabetes (T2D) in obese subjects is poorly documented. Rodent models have been set up in an attempt to better understand of the differential effect of a prolonged metabolic stress induced by a high fat diet on glycaemic control according to the genetic background. In utero growth retardation resulting from a hypocaloric diet in pregnant rats induces a dramatic alteration of the development of islet cells leading to diabetes and insulin secretory defects in adult age. Experimentally induced diabetes in rodents results in hyperglycaemia and hyperinsulinemia in the fetus related to accelerated endocrine pancreas maturation responsible for the onset of diabetes in the adult. Deranged metabolic environment during fetal life may therefore further contribute to the onset of diabetes in the adult. Normal mouse strains with different genetic backgrounds show a wide range of responses to a high fat diet, with strains resistant to the diet and other more or less sensitive to the diet, the most sensitive exhibiting obesity diabetes and, insulin deficiency. The inability of the β cell to respond to the increased insulin demand related to insulin resistance seems to be pivotal in the pathophysiologic process and a new notion is emerging: "nutritional genetics" which studies the influence of nutrients on gene expression., (© 2013 médecine/sciences – Inserm.)
- Published
- 2013
- Full Text
- View/download PDF
11. Peripheral injections of melanin-concentrating hormone receptor 1 antagonist S38151 decrease food intake and body weight in rodent obesity models.
- Author
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Della-Zuana O, Audinot V, Levenez V, Ktorza A, Presse F, Nahon JL, and Boutin JA
- Abstract
The compound S38151 is a nanomolar antagonist that acts at the melanin-concentrating hormone receptor 1 (MCH(1)). S38151 is more stable than its purely peptide counterpart, essentially because of the blockade of its N-terminus. Therefore, its action on various models of obesity was studied. Acute intra-cerebroventricular (i.c.v.) administration of S38151 in wild-type rats counteracted the effect of the stable precursor of melanin-concentrating hormone (MCH), NEI-MCH, in a dose-dependent manner (from 0.5 to 50 nmol/kg). In genetically obese Zucker fa/fa rats, daily i.c.v. administration of S38151 induced dose-dependent (5, 10, and 20 nmol/kg) inhibition of food intake, water intake, and body weight gain, as well as increased motility (maximal effect observed at 20 nmol/kg). In Zucker fa/fa rats, intraperitoneal injection of S38151 (30 mg/kg) induced complete inhibition of food consumption within 1 h. Daily intraperitoneal injection of S38151 (10 and 30 mg/kg) into genetically obese ob/ob mice or diet-induced obese mice is able to limit body weight gain. Furthermore, S38151 administration (10 and 30 mg/kg) does not affect food intake, water intake, or body weight gain in MCHR1-deleted mice, demonstrating that its effects are linked to its interaction with MCH(1). These results validate MCH(1) as a target of interest in obesity. S38151 cannot progress to the clinical phase because it is still too poorly stable in vivo.
- Published
- 2012
- Full Text
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12. Neuropeptide Y Y5 receptor antagonists as anti-obesity drugs.
- Author
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Levens NR and Della-Zuana O
- Subjects
- Animals, Eating physiology, Humans, Mice, Mice, Knockout, Neuropeptide Y physiology, Anti-Obesity Agents pharmacology, Receptors, Neuropeptide Y antagonists & inhibitors
- Abstract
Neuropeptide Y (NPY) is present in the hypothalamus, where it is believed to play a key role in the control of food intake. Evidence for this assertion has come from studies demonstrating that acute administration of NPY into the hypothalamus or into the brain ventricles leads to increased food intake. In the case of chronic administration, the hyperphagic effects of NPY are prolonged, leading to the development of an obese state. NPY levels in the hypothalamus are temporally correlated with food intake and are markedly elevated in response to energy depletion. However, attempts to demonstrate an important role for NPY in the control of food intake using NPY knockout mice, NPY antisense oligodeoxynucleotides and anti-NPY antibodies has produced equivocal results. Despite this, many pharmaceutical companies have moved ahead with the search for antagonists of NPY receptor subtypes as appetite suppressant/anti-obesity agents. Antagonists of the NPY Y5 subtype seemed initially promising since analogs of NPY with high selectivity for this receptor strongly stimulated food intake. However, once again, attempts to inhibit the signaling of NPY through the NPY Y5 receptor produced equivocal effects on food intake. Many thousands of NPY Y5 antagonists have been made which fall into two main categories: those that influence food intake and those that do not. Those compounds that do inhibit food intake appear to do so by interactions with non-NPY Y5 related mechanisms. Thus, current evidence would suggest that antagonists of NPY acting through the NPY Y5 receptor subtype will not be useful appetite suppressant/anti-obesity agents.
- Published
- 2003
13. Appetite suppressants: problems and pitfalls of drug discovery.
- Author
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Levens N and Della-Zuana O
- Subjects
- Animals, Appetite Depressants administration & dosage, Appetite Depressants toxicity, Drug Design, Drug Evaluation, Preclinical, Feeding Behavior drug effects, Humans, Pharmacology, Appetite Depressants pharmacology
- Published
- 2003
14. Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague-Dawley rats.
- Author
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Della-Zuana O, Presse F, Ortola C, Duhault J, Nahon JL, and Levens N
- Subjects
- Agouti-Related Protein, Animals, Body Weight, Carrier Proteins genetics, DNA Primers, Dose-Response Relationship, Drug, Drug Administration Schedule, Gene Expression Regulation, Hypothalamic Hormones administration & dosage, Hypothalamic Hormones metabolism, Intercellular Signaling Peptides and Proteins, Male, Melanins administration & dosage, Melanins metabolism, Nerve Tissue Proteins genetics, Neuropeptides genetics, Neurotensin genetics, Orexins, Pituitary Hormones administration & dosage, Pituitary Hormones metabolism, Polymerase Chain Reaction, Proteins genetics, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Rats, Wistar, Eating drug effects, Hypothalamic Hormones pharmacology, Intracellular Signaling Peptides and Proteins, Melanins pharmacology, Neuropeptide Y genetics, Pituitary Hormones pharmacology
- Abstract
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.
- Published
- 2002
- Full Text
- View/download PDF
15. Appetite-boosting property of pro-melanin-concentrating hormone(131-165) (neuropeptide-glutamic acid-isoleucine) is associated with proteolytic resistance.
- Author
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Maulon-Feraille L, Della Zuana O, Suply T, Rovere-Jovene C, Audinot V, Levens N, Boutin JA, Duhault J, and Nahon JL
- Subjects
- Amino Acid Sequence, Animals, Appetite Stimulants administration & dosage, CHO Cells, Calcium Signaling drug effects, Calcium Signaling physiology, Cell Line, Cerebral Ventricles drug effects, Cricetinae, Cyclic AMP pharmacology, Humans, Hypothalamic Hormones administration & dosage, Hypothalamic Hormones chemistry, Injections, Intraventricular, Kidney, Kinetics, Male, Molecular Sequence Data, Peptide Fragments administration & dosage, Protein Precursors administration & dosage, Protein Precursors chemistry, Rats, Rats, Wistar, Transfection, Appetite Stimulants pharmacology, Cerebral Ventricles physiology, Feeding Behavior drug effects, Hypothalamic Hormones pharmacology, Peptide Fragments pharmacology, Protein Precursors pharmacology
- Abstract
Melanin-concentrating hormone (MCH) is a cyclic neuropeptide, with a major role in stimulation of feeding behavior in mammals. MCH signals in the brain occur via two seven-transmembrane G protein-coupled receptors, namely MCH1 (SLC-1, MCH(1), MCH-R1, or MCH-1R) and MCH2 (SLT, MCH(2), MCH-R2, or MCH-2R). In this study, we demonstrate that the pro-MCH(131-165) peptide neuropeptide-glutamic acid-isoleucine (NEI)-MCH is more potent than MCH in stimulating feeding in the rat. Using rat MCH1-expressed human embryonic kidney 293 cells, we show that NEI-MCH exhibits 5-fold less affinity in a binding assay and 2-fold less potency in a cAMP assay than MCH. A similar 7- to 8-fold shift in potency was observed in a Ca(2+)(i) assay using rat MCH1 or human MCH2-transfected Chinese hamster ovary cell models. This demonstrates that NEI-MCH is not a better agonist than MCH at either of the MCH receptors. Then, we compared the proteolysis resistance of MCH and NEI-MCH to rat brain membrane homogenates and purified proteases. Kinetics of peptide degradation using brain extracts indicated a t(1/2) of 34.8 min for MCH and 78.5 min for NEI-MCH with a specific pattern of cleavage of MCH but not NEI-MCH by exo- and endo-proteases. Furthermore, MCH was found highly susceptible to degradation by aminopeptidase M and endopeptidase 24.11, whereas NEI-MCH was fully resistant to proteolysis by these enzymes. Therefore, our results strongly suggest that reduced susceptibility to proteases of NEI-MCH compared with MCH account for its enhanced activity in feeding behavior. NEI-MCH represents therefore the first MCH natural functional "superagonist" so far described.
- Published
- 2002
- Full Text
- View/download PDF
16. SLC-1 receptor mediates effect of melanin-concentrating hormone on feeding behavior in rat: a structure-activity study.
- Author
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Suply T, Della Zuana O, Audinot V, Rodriguez M, Beauverger P, Duhault J, Canet E, Galizzi JP, Nahon JL, Levens N, and Boutin JA
- Subjects
- Animals, Cell Line, Cell Membrane drug effects, Cell Membrane metabolism, Cloning, Molecular, Cyclic AMP metabolism, Injections, Intraventricular, Male, Oligopeptides pharmacology, Poly A metabolism, RNA, Messenger biosynthesis, Rats, Rats, Wistar, Recombinant Proteins metabolism, Structure-Activity Relationship, Feeding Behavior drug effects, Hypothalamic Hormones pharmacology, Melanins pharmacology, Pituitary Hormones pharmacology, Receptors, Somatostatin drug effects
- Abstract
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.
- Published
- 2001
17. Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade.
- Author
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Della Zuana O, Sadlo M, Germain M, Félétou M, Chamorro S, Tisserand F, de Montrion C, Boivin JF, Duhault J, Boutin JA, and Levens N
- Subjects
- Animals, Dose-Response Relationship, Drug, Eating drug effects, Encephalitis, Energy Intake genetics, Injections, Intraventricular, Male, Naphthalenes administration & dosage, Obesity metabolism, Pyrimidines administration & dosage, Rats, Rats, Wistar, Rats, Zucker, Receptors, Muscarinic metabolism, Receptors, Serotonin metabolism, Time Factors, Eating physiology, Energy Intake drug effects, Naphthalenes pharmacology, Neuropeptide Y metabolism, Pyrimidines pharmacology, Receptors, Neuropeptide Y antagonists & inhibitors
- Abstract
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
- Published
- 2001
- Full Text
- View/download PDF
18. Preparation and pharmacological profile of 2-trifluoromethyl-benzo(8,9)-1,3-diaza-spiro (4,6)-undeca-2,8-diene and its enantiomers as new anti-obesity agents.
- Author
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Boussard MF, Guette JP, Wierzbicki M, Beal P, Fournier J, Boulanger M, Della-Zuana O, and Duhault J
- Subjects
- Animals, Anti-Obesity Agents pharmacology, Appetite Depressants chemical synthesis, Appetite Depressants pharmacology, Biogenic Monoamines metabolism, Blood Pressure drug effects, Brain Chemistry drug effects, Eating drug effects, Fluorobenzenes chemical synthesis, Fluorobenzenes pharmacology, In Vitro Techniques, Male, Obesity drug therapy, Rats, Rats, Sprague-Dawley, Rats, Wistar, Rats, Zucker, Receptors, Drug drug effects, Spiro Compounds chemical synthesis, Spiro Compounds pharmacology, Stereoisomerism, Anti-Obesity Agents chemical synthesis
- Abstract
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.
- Published
- 2000
- Full Text
- View/download PDF
19. Food intake regulation in rodents: Y5 or Y1 NPY receptors or both?
- Author
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Duhault J, Boulanger M, Chamorro S, Boutin JA, Della Zuana O, Douillet E, Fauchère JL, Félétou M, Germain M, Husson B, Vega AM, Renard P, and Tisserand F
- Subjects
- Animals, Arginine analogs & derivatives, Arginine metabolism, Arginine pharmacology, Blood Pressure drug effects, CHO Cells, COS Cells, Cricetinae, Female, Humans, Male, Mice, Mice, Obese, Naphthalenes pharmacology, Pyrimidines pharmacology, Rabbits, Rats, Rats, Sprague-Dawley, Rats, Wistar, Eating drug effects, Receptors, Neuropeptide Y physiology
- Abstract
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.
- Published
- 2000
20. General pharmacology of S 15261, a new concept for treatment of diabetes.
- Author
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Duhault J, Berger S, Boulanger M, Della Zuana O, Lacour F, and Wierzbicki M
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin antagonists & inhibitors, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Biogenic Monoamines metabolism, Blood Glucose metabolism, Blood Pressure drug effects, Brain Chemistry drug effects, Feeding Behavior drug effects, Female, Fluorenes pharmacokinetics, Fluorenes toxicity, Guinea Pigs, Male, Mice, Pain Measurement drug effects, Radioligand Assay, Rats, Rats, Sprague-Dawley, Reaction Time drug effects, Receptors, Cell Surface drug effects, Receptors, Cell Surface metabolism, Serotonin Receptor Agonists pharmacology, Fluorenes pharmacology, Insulin Resistance physiology
- Abstract
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.
- Published
- 1998
21. [Biochemical changes in 24-month-old Wistar rats].
- Author
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Roman F, Della Zuana O, Lonchampt M, Saint Romas G, and Duhault J
- Subjects
- 3,4-Dihydroxyphenylacetic Acid metabolism, Acetylcholinesterase metabolism, Aging, Animals, Choline metabolism, Choline O-Acetyltransferase metabolism, Collagen metabolism, Dopamine analogs & derivatives, Dopamine metabolism, Hippocampus enzymology, Homovanillic Acid metabolism, Hydroxyindoleacetic Acid metabolism, Lipid Peroxides metabolism, Male, Malondialdehyde blood, Malondialdehyde metabolism, Quinuclidinyl Benzilate metabolism, Rats, Rats, Inbred Strains, Serotonin metabolism, Skin metabolism, Corpus Striatum metabolism, Hippocampus metabolism, Pons metabolism
- Abstract
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.
- Published
- 1984
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