Neuropeptide Y receptors as targets of obesity treatment

The prevalence of obesity continues to increase throughout the world and the burden of obesity and related co-morbidities is large. However, existing drug therapies for obesity are limited, and agents with high efficacy, safety and tolerability are expected to better meet patient needs and lead to more substantial commercial success. Neuropeptide Y (NPY) is thought to have a major role in the physiological control of energy homeostasis. Multiple receptor subtypes mediate the effects of NPY on energy homeostasis and many pharmacological studies indicate the involvement of Y1 and Y5 receptor subtypes in NPY-induced feeding and obesity. In addition, recent observations with gut-derived peptides suggest a role for Y2 and Y4 receptor subtypes as catabolic receptors. This article highlights and reviews recent observations and patents regarding NPY receptor ligands for drug discovery as antiobesity agents.     

NPY receptors as potential targets for anti-obesity drug development

The neuropeptide Y system has proven to be one of the most important regulators of feeding behaviour and energy homeostasis, thus presenting great potential as a therapeutic target for the treatment of disorders such as obesity and at the other extreme, anorexia. Due to the initial lack of pharmacological tools that are active in vivo, functions of the different Y receptors have been mainly studied in knockout and transgenic mouse models. However, over recent years various Y receptor selective peptidic and non-peptidic agonists and antagonists have been developed and tested. Their therapeutic potential in relation to treating obesity and other disorders of energy homeostasis is discussed in this review.     

Neuropeptide Y Y2 receptor in health and disease

We briefly survey the current knowledge and concepts regarding structure and function of the neuropeptide Y Y2 receptor and its agonists, especially as related to pharmacology of the receptor and its roles in pathological processes. Specific structural features are considered that could be responsible for the known compartmentalization and participation of the receptor in cell and tissue organization. This is further discussed in relation to changes of levels of the Y2 receptor in pathological conditions (especially in epilepsy and drug abuse), to endocytosis and recycling, and to participation in wound healing, retinopathy and angiogenesis. Properties of the receptor and of Y2 agonists are considered and reviewed in connection to the negative regulation of transmitter release, feeding, mood and social behavior. The possible involvement of the Y2 receptor in diabetes, carcinogenesis and bone formation is also reviewed.     

Orlistat: its current status as an anti-obesity drug

Orlistat is a non-centrally acting anti-obesity agent that acts locally in the gastrointestinal tract to inhibit lipase, an enzyme that is crucial for the digestion of long-chain triglycerides. At the recommended dose of 120 mg three times daily, orlistat inhibits dietary fat absorption by about 30%. Over a 1-year period, obese patients taking orlistat in combination with a hypocaloric diet show a reduction of 2–5 kg over the weight decrease with placebo. When continued for a second year in combination with a weight maintenance diet, orlistat reduces weight regain compared to placebo-treated patients. Orlistat in combination with dietary intervention is also associated with beneficial effects on cardiovascular risk factors including total and low-density lipoprotein cholesterol, blood pressure and plasma glucose. It is not known if orlistat has any impact on clinical outcomes such as myocardial infarction, stroke and sudden death. Orlistat has not been compared with other anti-obesity agents.     

Neuropeptide Y and energy homeostasis: insights from Y receptor knockout models

A complex system has evolved to regulate food intake and to maintain energy homeostasis. A series of short-term hormonal and neural signals that derive from the gastrointestinal tract, such as cholecystokinin (CCK), pancreatic polypeptide (PP) and peptide YY-(3–36), recently discovered to regulate meal size. Others such as ghrelin initiate meals, and insulin and leptin, together with circulating nutrients, indicate long-term energy stores. All these signals act on central nervous system sites which converge on the hypothalamus, an area that contains a large number of peptide and other neurotransmitters that influence food intake with neuropeptide Y (NPY) being one of the most prominent ones. Five Y receptors are known which mediate the action of neuropeptide Y and its two other family members, peptide YY and pancreatic polypeptide. Elevated neuropeptide Y expression in the hypothalamus leads to the development of obesity and its related phenotypes, Type II diabetes and cardiovascular disease. The limited availability of specific pharmacological tools and the considerable number of Y receptors have made it difficult to delineate their individual contributions to the regulation of energy homeostasis. However, recent studies analysing transgenic and knockout neuropeptide Y and Y receptor mouse models have started to unravel some of the individual functions of these Y receptors potentially also helping to develop novel therapeutics for a variety of physiological disorders including obesity.     

Neuropeptide Y: identification of the binding site

Based on the hypothetical 3D structure of neuropeptide Y (NPY), NPY 1-4-Aca-25-36, a 17 amino acid analogue, has been synthesized replacing the sequence NPY 5-24 by ε-aminocaproic acid (Aca). This low-molecular weight deletion analogue showed nearly comparable receptor affinity to NPY. In order to elucidate the structural requirements for receptor recognition each amino acid of 1-4-Aca-25-36 was exchanged by its D-enantiomer, glycine and L-alanine. In addition distinct amino acids were replaced by closely related residues. Multiple peptide synthesis was applied using Fmoc-strategy and BOP activation. Binding assay was performed on rabbit kidney membrane preparations. The results of structure affinity studies suggest that the C-terminal tetrapeptide NPY 33-36 is essential for receptor recognition.     

Central Neuropeptide Y Modulates Binge-Like Ethanol Drinking in C57BL/6J Mice via Y1 and Y2 Receptors

Frequent binge drinking has been linked to heart disease, high blood pressure, type 2 diabetes, and the development of ethanol dependence. Thus, identifying pharmaceutical targets to treat binge drinking is of paramount importance. Here we employed a mouse model of binge-like ethanol drinking to study the role of neuropeptide Y (NPY). To this end, the present set of studies utilized pharmacological manipulation of NPY signaling, immunoreactivity (IR) mapping of NPY and NPY receptors, and electrophysiological recordings from slice preparations of the amygdala. The results indicated that central infusion of NPY, a NPY Y1 receptor (Y1R) agonist, and a Y2R antagonist significantly blunted binge-like ethanol drinking in C57BL/6J mice (that achieved blood ethanol levels >80 mg/dl in control conditions). Binge-like ethanol drinking reduced NPY and Y1R IR in the central nucleus of the amygdala (CeA), and 24 h of ethanol abstinence after a history of binge-like drinking promoted increases of Y1R and Y2R IR. Electrophysiological recordings of slice preparations from the CeA showed that binge-like ethanol drinking augmented the ability of NPY to inhibit GABAergic transmission. Thus, binge-like ethanol drinking in C57BL/6J mice promoted alterations of NPY signaling in the CeA, and administration of exogenous NPY compounds protected against binge-like drinking. The current data suggest that Y1R agonists and Y2R antagonists may be useful for curbing and/or preventing binge drinking, protecting vulnerable individuals from progressing to the point of ethanol dependence.     

Preparation of fluorescent nonpeptidic neuropeptide Y receptor ligands: analogues of the quinazoline-type anti-obesity Y5 antagonist CGP 71683A

As part of a programme to develop fluorescence-based methods for the study of the interactions between G-protein coupled receptors (GPCRs) and their ligands the preparation of low molecular weight fluorescence-labelled neuropeptide Y (NPY) Y(5) antagonists is reported. The naphthylsulfonyl group in the potent quinazoline-type NPY Y(5) receptor antagonist CGP 71683A was replaced with a dansyl, nitrobenzoxadiazole (NBD) or acridine-9-carbonyl group. In radioligand binding studies on human Y(5) receptor expressing HEC-1B cells the substances labelled with acridine (K(i) 311 nM) and NBD (K(i) > 1000 nM) proved to be moderately active or inactive, respectively. By contrast, a K(i) value of 49 nM was found for the dansyl analogue compared to 2 nM for CGP 71683A. No binding to Y(1) receptors (SK-N-MC cells, displacement of [(3)H]propionyl-NPY) was detected for the new compounds at concentrations 相似文献   

Neuropeptide Y2 receptors as drug targets for the central regulation of body weight

During the past decade, a detailed understanding has emerged of the aminergic and peptidergic neural pathways present within the brain that regulate appetite. Central among the peptide regulators is neuropeptide Y (NPY), a potent orexigenic agent that acts through five different receptor subtypes. Efforts to find novel appetite suppressant drugs that inhibit the interaction of NPY with either the NPY Y1 or NPY Y5 receptor subtypes have proven disappointing. Attempts have now been made to identify an NPY Y2 stimulator that will suppress appetite. Within the hypothalamus, NPY Y2 receptors have a predominantly presynaptic location where they act to inhibit NPY release. Stimulation of NPY Y2 receptors with synthetic peptide ligands or the gut derived peptide PY3-36 has been shown to reduce food intake. The NPY Y2 receptor has a wide distribution both within the brain and in the periphery. Stimulation of the NPY Y2 subtype at these sites produces a wide array of effects unrelated to changes in food intake. In consequence, the administration of both endogenous and exogenous agonists of the NPY Y2 receptor is likely to cause side effects, particularly regarding pituitary hormone release, as well as on the cardiovascular and gastrointestinal systems. The possibility that long-term NPY Y2 agonism could cause bone thinning and retinal angiogenesis are of particular concern and will need to be investigated as drug discovery moves forward.     

Modulation of neuropeptide Y receptors for the treatment of obesity

Background: Neuropeptide Y (NPY) has been demonstrated to have critical roles in the physiological control of appetite and energy homeostasis through NPY Y1, Y2, Y4 and Y5 receptors. A number of synthetic ligands for NPY receptor subtypes have been developed to date, with Y5 receptor antagonists and Y2 and Y4 receptor agonists advancing into clinical trials. Methods: A survey of the scientific and patent literature since mid-2006 is presented. Conclusion: In addition to the specific modulation of respective NPY receptor subtypes, recent investigations have revealed that modulation of multiple NPY receptor subtypes produces additive or even synergistic anti-obesity effects. Development of reliable small molecule Y1, Y2 and Y4 receptor ligands would greatly accelerate investigations and drug discovery.     

The discovery and status of sibutramine as an anti-obesity drug

Sibutramine is a serotonin–norepinephrine reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. Though sibutramine was originally evaluated for possible use as an antidepressant, its research development was eventually redirected to evaluate it as an anorexiant. The pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely due to a combination of reduced appetite, feelings of satiety, and possibly the induction of thermogenesis. Its efficacy for inducing an initial weight-loss and the subsequent maintenance of the weight-loss is well proven in short- and long-term clinical trials of up to 2 years duration. In general, sibutramine has been well tolerated. Increases in blood pressure and heart rate are possible adverse effects that require regular monitoring. Sibutramine is one of the few established and well-proven agents for obesity available for use today and should be considered effective in the management of patients requiring pharmacotherapy as part of the multi-modal approach to weight-loss.     

Synthesis and Neuropeptide Y Y1 Receptor Antagonistic Activity of N,N-Disubstituted ω-Guanidino- and ω-Aminoalkanoic Acid Amides

Potent arpromidine-type histamine H₂ receptor agonists such as BU-E-76 (He 90481) were among the first non-peptides reported to display weak neuropeptide Y (NPY) Y₁ receptor antagonist activity. In search of new chemical leads for the development of more potent NPY antagonists, a series of N,N-disubstituted ω-guanidino and ω-aminoalkanoic acid amides were synthesized on the basis of structure-activity relationships and molecular modeling studies of arpromidine and related imidazolylpropylguanidines. In one group of compounds the imidazole ring was retained whereas in the second group it was replaced with a phenol group representing a putative mimic of Tyr³⁶ in NPY. Although the substitution patterns have not yet been optimized, the title compounds are NPY Y₁ antagonists in human erythroleukemia (HEL) cells (Ca²⁺ assay) achieving pKB values in the range of 6.3–6.6. For representative new substances tested in the isolated guinea pig right atrium histamine H₂ receptor agonism could not be found. In the N-(diphenylalkyl)amide series, compounds with a trimethylene chain were more active Y₁ antagonists than the ethylene homologs. Concerning the spacer in the ω-amino or ω-guanidinoalkanoyl portion, the best activity was found in compounds with a four- or five-membered alkyl chain or a 1,4-cyclohexylene group. Surprisingly, in contrast to the phenol series, in the imidazole series the compounds with a side chain amino group turned out to be considerably more potent than the corresponding strongly basic guanidines. Thus, the structure-activity relationships appear to be different for the diphenylalkylamide NPY antagonists with one or two basic groups.     

Neuropeptide Y (NPY) inhibits spontaneous contraction of the mouse atrium by possible activation of the NPY1 receptor

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Sibutramine: current status as an anti-obesity drug and its future perspectives

Background: Obesity has become a global epidemic with recent estimates of > 400 million obese adults. Despite this, there are few safe and effective pharmacological interventions for obesity. Sibutramine is a weight loss agent, for use as an adjuvant to a comprehensive program of calorie restriction, exercise and behavioral therapy. Objective: The goal of this article is to review the available literature of pharmacological interventions for obesity and specifically to examine data with sibutramine for the short term on safety and efficacy for weight loss. Methods: The literature on sibutramine was reviewed after a PubMed and Medline search in March 2008. All randomized clinical trails were reviewed. Results/conclusions: Sibutramine appears to be safe and effective in producing clinically significant weight loss for up to 1 year. Longer prospective clinical studies with sibutramine are needed to evaluate its safety (effect on blood pressure) and ability to maintain weight loss, improve metabolic profiles and reduce the risk of cardiovascular diseases.     

Adenosine receptors as targets for drug development

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A(1), A(2A), A(2B) and A(3). Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma.     

Cerebrospinal Fluid Neuropeptide Y Levels in Major Depression and Reported Childhood Trauma

Background:

Neuropeptide Y (NPY) may enhance resilience to chronic stress. Low brain NPY reported in major depression may normalize in response to antidepressants.

Methods:

In this study, we examined the relationship of reported childhood trauma to cerebrospinal fluid (CSF) NPY–like immunoreactivity (NPY-LI) in 61 medication-free major depressive disorder (MDD) patients and 20 matched healthy volunteers.

Results:

Higher CSF NPY-LI was found in MDD compared to the healthy volunteer group (p = 0.01). A positive correlation of CSF NPY-LI with more adverse childhood trauma (p = 0.001) may be indicative of an intact but insufficient NPY-related stress response.

Conclusions:

We hypothesize that differences in published results may be explained by the existence of two groups of MDD in terms of CSF NPY levels: MDD with low CSF NPY prior to stress or in response to stress, and those with robust NPY responses to stress. Future studies should confirm the two groups and seek the molecular mechanism for their differences.     

Neuropeptide Y and somatostatin immunoreactivity in the rat hippocampus after moderate hypoxia

Transient moderate hypoxia has been previously shown to exert a potent protective role to subsequently applied convulsant drugs. We now investigated neuropeptide Y and somatostatin immunoreactivities seven days after moderate hypoxia (9% O₂ in N₂ for two times 8 h) in the hippocampus of the rat. A slight reduction of somatostatin immunoreactive cells was observed in the hilus of the dorsal and ventral hippocampus. At the same time, the total number of neuropeptide Y immunoreactive neurons was increased in this area due to a pronounced increase in staining of presumable basket cells. There was also increased staining of neuropeptide Y positive fibers in the outer molecular layer. Our data suggest activation of neuropeptide Y containing interneurons after a moderate or a mild transient hypoxia. Activation of these inhibitory neurons may contribute to the protective effect of this treatment.     

Neuropeptide Y as a stimulator of Na+-dependent Ca2+ efflux from freshly isolated adult rat cardiomyocytes

Several physiological stimuli cause a rise in intracellular Ca²⁺ concentration ([Ca²⁺]_i) in cardiomyocytes. This increased [Ca²⁺]_i must be restored to physiological resting level to ensure response to further stimuli. In the present study, we examined the effect of neuropeptide Y (NPY), which is secreted from certain adrenergic or non-adrenergic neurons, on Ca²⁺ efflux from freshly isolated, quiescent adult rat cardiomyocytes. The isolated cardiomyocytes were preloaded with ⁴⁵CaCl₂ for 1 h. Then, the fractional release of ⁴⁵Ca²⁺ from the cells was measured. NPY stimulated the efflux of ⁴⁵Ca²⁺ from isolated adult rat cardiomyocytes in a concentration-dependent manner (10^–8 M to 10^–6 M). NPY (10^–6 M)-induced Ca²⁺ efflux was 2.0 ± 0.16% of the total cellular content. The ⁴⁵Ca²⁺ efflux from the cells was also stimulated by Y₁ receptor agonist, [Leu³¹, Pro³⁴]NPY, but not by Y₂ receptor agonist, NPY_13–36. The effect of NPY was inhibited by a peptide NPY inhibitor, NPY_18–36 and a non-peptide NPY inhibitor, benextramine to a similar extent. From these results, it is conceivable that the effect of NPY on Ca²⁺ efflux from cardiomyocytes is mediated through Y₁ receptors. It was also observed that NPY caused a rise in [Ca²⁺]_i to almost 150 nM. NPY-stimulated ⁴⁵Ca²⁺ efflux was not affected by removal of extracellular Ca²⁺, but was dependent on the presence of extracellular Na⁺. Moreover, NPY caused a ²²Na⁺ influx into the cells of about 1.6-fold over the basal value which was inhibited by amiloride and 5-(N,N-dimethyl)-amiloride, known Na⁺/Ca²⁺ exchange inhibitors. In addition, isoproterenol also caused ⁴⁵Ca²⁺ efflux from the cells and which was enhanced by the addition of NPY. These results suggest that NPY stimulates extracellular Na⁺-dependent ⁴⁵Ca²⁺ efflux from freshly isolated adult rat cardiomyocytes, probably through its stimulatory effect on plasma membrane Y₁ receptors with which NPY may couple during Na⁺/Ca²⁺ exchange. Received: 21 May 1997 / Accepted: 26 August 1997     

Metabotropic glutamate receptors as targets for new drug development

The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.