Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults

Erondu, Ngozi; Gantz, Ira; Musser, Bret J.; Suryawanshi, Shailaja; Mallick, Madhuja; Addy, Carol; Côté, Josée; Bray, George A.; Fujioka, Ken; Bays, Harold; Hollander, Priscilla; Sanabria-Bohórquez, Sandra M.; Eng, Wai-si; Långström, Bengt; Hargreaves, Richard; Burns, H. Donald; Kanatani, Akio; Fukami, Tatsuki; MacNeil, Douglas J.; Gottesdiener, Keith; Amatruda, John M.; Kaufman, Keith D.; Heymsfield, Steven B.

doi:10.1016/j.cmet.2006.08.002

Cited by 173 publications

(138 citation statements)

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“…8a Recently, it was reported that administration of a potent and highly selective NPY Y5 receptor antagonist, MK-557, resulted in modest weight loss in obese human subjects. 12 Considering the well-tolerated Y5 antagonist treatment in humans and possibility of the combination therapy with Y1 antagonists, development of safe and mechanistically validated Y5 antagonists is of considerable importance. 11d We previously reported the discovery of a potent imidazoline class of Y5 antagonists, 1a and 1b ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

et al. 2009

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A series of novel imidazoline derivatives was synthesized and evaluated as neuropeptide Y (NPY) Y5 receptor antagonists. Optimization of previously reported imidazoline leads, 1a and 1b, was attempted by introduction of substituents at the 5-position on the imidazoline ring and modification of the bis(4-fluorphenyl) moiety. A number of potent derivatives without human ether-a-go-go related gene potassium channel (hERG) activity were identified. Selected compounds, including 2a, were shown to have excellent brain and CSF permeability. Compound 2a displayed a suitable pharmacokinetic profile for chronic in vivo studies and potently inhibited D-Trp 34 NPY-induced acute food intake in rats. Oral administration of 2a resulted in a potent reduction of body weight in a diet-induced obese mouse model.

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Section: Introductionmentioning

confidence: 99%

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

et al. 2009

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“…Nonetheless, some Y5 receptor antagonists have been tested in humans. The orally active Y5 receptor antagonist MK-0557 induced weight loss statistically greater than placebo control after one year of treatment, but the magnitude of this effect was not clinically meaningful [23]. The orally active Y5 receptor antagonist S-2367 resulted in a small reduction in body weight compared to placebo-treated controls when administered to obese subjects in conjunction with a 500-800 kcal/day energy deficit [22].…”

Section: Neuropeptide Ymentioning

confidence: 99%

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

Greenwood

Bloom²,

Murphy

2011

Rev Diabet Stud

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■ AbstractIt is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.

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“…The Y5 antagonist MK0557 was recently shown to induce only modest weight loss (3.4 kg) compared with placebo (1.8 kg) in a 52-week study. These results led the authors to conclude that Y5 receptor activation is involved in energy homeostasis in man; however, selective blockade of this receptor alone was insufficient to produce clinically meaningful weight loss [47].…”

Section: Neuropeptide Y Antagonistsmentioning

confidence: 99%

“…NPY levels are regulated by leptin and other peripheral modulators (e.g. gut hormones); following a meal when leptin levels are low,NPY activity is reduced [47].Conversely, NPY levels are elevated during hunger and energy depletion [21]. Selective NPY antagonists, particularly targeting NPY5 receptors, inhibit feeding and reduce body weight in models of obesity [46].…”

Section: Neuropeptide Y Antagonistsmentioning

confidence: 99%

New central targets for the treatment of obesity

Sargent

Moore

2009

Brit J Clinical Pharma

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The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation 'New central targets for the treatment of obesity ' (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008). Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT2c and 5-HT6). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH1 receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders. The obesity problemObesity is a major global health problem and rates of obesity [body mass index (BMI) >30 kg m -2 ] have risen steadily year on year. Recent figures show an incidence of obesity of more than 1 in 4 in many parts of the USA [1]. These high rates are similar in other developed countries and the incidence of weight gain is increasing in less developed regions. Obesity is not just a cosmetic or lifestyle illness but leads to many life-threatening health complications. As the BMI increases the incidence of metabolic disorders (Type 2 diabetes), hypertension, cancer and musculoskeletal problems increases [1][2][3]. In 1999, Calle et al. reported mortality rates for all causes doubled when the BMI increased from 25 to >35 [4].The annual direct healthcare costs associated with obesity in the USA are in excess of $93 billion [5]. Particularly worrying is the fact that the incidence of obesity in children and young adults is on the increase, with some reports suggesting that up to 25% of children may be obese. The long-term health implications of these findings are far reaching and suggest that for the first time intergenerational increase in life expectancy will not occur and these children will have a shorter life span than their parents because of health complications associated with weight gain [6] (Figure 1).Obesity occurs when the balance between energy input (food intake) and energy expenditure (exercise, activity) is disrupted, i.e. more food is consumed than utilized, leading to excess fat stores being laid down. Although for some people a calorie-restricted diet and exercise can lead to a reduction in weight gain, for many peop...

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Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults

Cited by 173 publications

References 44 publications

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

Discovery of Tetrasubstituted Imidazolines as Potent and Selective Neuropeptide Y Y5 Receptor Antagonists: Reduced Human Ether-a-go-go Related Gene Potassium Channel Binding Affinity and Potent Antiobesity Effect

Peptides and Their Potential Role in the Treatment of Diabetes and Obesity

New central targets for the treatment of obesity

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