Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade

Zuana, Odile Della; Sadlo, Marjorie; Germain, Martine; Félétou, Michel; Chamorro, Susana; Tisserand, F; Montrion, Catherine de; Boivin, Jean‐François; Duhault, J; Boutin, Jean A.; Levens, Nigel

doi:10.1038/sj.ijo.0801472

Cited by 55 publications

(21 citation statements)

References 56 publications

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“…To investigate its cross-reactivity, CGP 71683A has recently been studied in a series of both NPY and non-NPY receptor binding assays (Table 5). 135 Surprisingly, CGP 71683A was found to have equally high affinity for the serotonin reuptake recognition site and for cholinergic muscarinic receptors in the rat brain as for the NPY Y 5 receptor. Reasonably high affinity for a 2 -adrenergic receptors was also observed -a finding in Appetite suppression S Chamorro et al agreement with the original published studies on this compound.…”

Section: Npy Receptor Subtypesmentioning

confidence: 99%

“…135 Inflammatory mediators have been shown to negatively affect food intake and could be a further explanation for the decreased appetite observed with this compound. 140 In accordance with the above studies, CGP 71683A has recently been shown to reduce food intake equally in both wild type and in NPY-knockout mice.…”

Section: Npy Receptor Subtypesmentioning

confidence: 99%

“…The binding affinities of each of these compounds to NPY receptor subtypes and a selected range of other receptors and binding sites were determined using previously described methods. 135 Where data are available at more than one dose the results are expressed as IC 50 s. We consider that an inhibition of ligand binding of more than 40% at 10 mM represents a significant interaction of the NPY antagonist with each studied receptor. NA ¼ not available.…”

Section: Npy Receptor Subtypesmentioning

confidence: 99%

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Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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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 Y 2 and NPY Y 5 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.

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Section: Npy Receptor Subtypesmentioning

confidence: 99%

Section: Npy Receptor Subtypesmentioning

confidence: 99%

Section: Npy Receptor Subtypesmentioning

confidence: 99%

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Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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“…193,194 Mixed ligands of neuropeptide Y 5 receptors and 5-HT transporters have also been described. 195 The real future of neuromodulatory peptidergic mechanisms may well lie in the multitarget universe, and it is hard to comprehend the persistent obsession with selective agents only. To reiterate, disappointing results with a selective agent do not necessarily imply therapeutic irrelevance but, rather, invite exploitation by means of a multitarget strategy.…”

Section: Figmentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

179

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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“…However, other authors reported no effects with their Y5-receptor blockers, 65 or suggested that the compound used in earlier studies 64 may have nonspecific effects. 66 Recent reports appear to again provide evidence for an important role of Y1 receptors in the regulation of feeding. 67 It is therefore still unclear which receptor subtype is the most promising target for therapeutically active NPY antagonists.…”

Section: Leptin Pathwaymentioning

confidence: 99%

Molecular pathways to obesity

2002

Int J Obes

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Obesity results from a chronic imbalance between energy intake and energy expenditure. Environmental factors, such as the increased availability of high caloric food or the decreased need for physical activity, contribute to its development and their influence is amplified by genetic predisposition. In recent years remarkable progress has been made in the understanding of the pathophysiology of obesity. Although most of the insights into the regulation of energy balance have been obtained in rodent models, the rare clinical cases of monogenic obesity provided evidence for the importance of several of these mechanisms in humans. The identification of leptin as a factor originating from adipose tissue and informing the brain about the status of energy reserves firmly established the concept of long-term regulation of body fat stores. The disappointing therapeutic results with leptin in obese patients could be explained by the fact that during evolution this hormone developed rather as a starvation signal than as an adiposity signal. It is conceivable that the pharmacological interference with mechanisms downstream of leptin, for example with the melanocortin pathway, might be therapeutically more promising. The discovery of new molecular mechanisms involved in the regulation of the differentiation and proliferation of adipocytes and the elucidation of their paracrine and endocrine functions have changed the traditional view of adipose tissue as an inert depot for triglycerides. The identification of new uncoupling proteins could modify the current concepts of the regulation of thermogenesis in humans. The remarkable progress in the identification of novel targets involved in the regualtion of energy balance should have a positive impact on the search for new antiobesity agents.

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Reduced food intake in response to CGP 71683A may be due to mechanisms other than NPY Y5 receptor blockade

Cited by 55 publications

References 56 publications

Appetite suppression based on selective inhibition of NPY receptors

Appetite suppression based on selective inhibition of NPY receptors

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Molecular pathways to obesity

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