Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y1 receptor antagonist

Antal‐Zimanyi, Ildiko; Bruce, Marc A.; LeBoulluec, Karen L.; Iben, Lawrence G.; Mattson, Gail K.; McGovern, Rachel T.; Hogan, John B.; Leahy, Christina; Flowers, Sharon C.; Stanley, Jennifer; Ortiz, Astrid; Poindexter, Graham S.

doi:10.1016/j.ejphar.2008.06.032

Cited by 33 publications

(30 citation statements)

References 36 publications

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“…Chronic administration of BMS-193885 suppressed feeding and body weight gain. However, although no behavioral side effects were identified, a number of rats fell ill following chronic administration [19]. Also, the drug is not orally available and induced adhesive peritonitis in these rats following intraperitoneal administration due to poor tissue absorption [19].…”

Section: Neuropeptide Ymentioning

confidence: 99%

“…However, J-115814 potently interacts with the I Kr potassium channel [18], suggesting that it could have cardiovascular side effects. Another Y1 receptor antagonist, BMS-193885, attenuates both NPY-induced and spontaneous nocturnal feeding following intraperitoneal administration to rats [19]. Chronic administration of BMS-193885 suppressed feeding and body weight gain.…”

Section: Neuropeptide Ymentioning

confidence: 99%

“…Several Y1 receptor antagonists have been administered to ro-dents, but most have associated safety concerns, and none have been tested in humans [18,19]. The Y1 receptor antagonist J-115814 inhibits feeding in lean C57BL/6 mice and in hyperphagic db/db mice, which lack leptin signaling, and in mice with diet-induced obesity (DIO) [20,21].…”

Section: Neuropeptide Ymentioning

confidence: 99%

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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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Section: Neuropeptide Ymentioning

confidence: 99%

Section: Neuropeptide Ymentioning

confidence: 99%

Section: Neuropeptide Ymentioning

confidence: 99%

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

Greenwood

Bloom²,

Murphy

2011

Rev Diabet Stud

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“…Scatchard analysis found that its inhibitory effect on [ 125 I]PYY binding to Y1 receptor in SK-N-MC cell membranes was noncompetitive. At the concentration of 50 nM, it reduced PYY binding capacity (B max of 1.1 to 0.3 nmol/mg protein) but had little effect on PYY binding affinity (K d = 1.1 ± 0.3 vs 1.2 ± 0.2 nM); meanwhile, a known competitive antagonist, BMS-193885, 21,22 at a concentration of 5 nM, did not affect PYY B max but did reduce its binding affinity (K d = 3.1 ± 0.9 nM).…”

mentioning

confidence: 99%

“…It also blocked centrally administrated NPY-induced food intake in rats and significantly reduced food intake and body weight in rats during chronic dosing of BMS-193885 (ip 10 mg/kg) for 44 days. 22 However, because BMS-193885 is not orally bioavailable, fenfluramine (1 and 3 mg/kg either orally or ip) was used instead, in these experiments, as a positive control; 2 was administrated 2−2.5 h before the onset of darkness, and the amount of food consumed during a 12 h period was recorded. As shown in Figure 6, the effect on food intake reached statistical significance for both doses tested during the 12 h period.…”

mentioning

confidence: 99%

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

Huang

Deshpande

et al. 2012

ACS Med. Chem. Lett.

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A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [ 125 I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6β)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC 50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague−Dawley rats, 2 significantly reduced food intake during a 12 h period.

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CCK, PYY and PP: The Control of Energy Balance

Simpson

Parker

Plumer

et al. 2011

Handbook of Experimental Pharmacology

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The control of food intake consists of neural and hormonal signals between the gut and central nervous system (CNS). Gut hormones such as CCK, PYY and PP signal to important areas in the CNS involved in appetite regulation to terminate a meal. These hormones can act directly via the circulation and activate their respective receptors in the hypothalamus and brainstem. In addition, gut vagal afferents also exist, providing an alternative pathway through which gut hormones can communicate with higher centres through the brainstem. Animal and human studies have demonstrated that peripheral administration of certain gut hormones reduces food intake and leads to weight loss. Gut hormones are therefore potential targets in the development of novel treatments for obesity and analogue therapies are currently under investigation.

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Pharmacological characterization and appetite suppressive properties of BMS-193885, a novel and selective neuropeptide Y1 receptor antagonist

Cited by 33 publications

References 36 publications

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

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

Discovery of a Novel Class of Bicyclo[3.1.0]hexanylpiperazines as Noncompetitive Neuropeptide Y Y1 Antagonists

CCK, PYY and PP: The Control of Energy Balance

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