Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists

2000 ◽  
Vol 78 (2) ◽  
pp. 143-149 ◽  
Author(s):  
Ants Kask ◽  
Helgi B Schiöth ◽  
Jaanus Harro ◽  
Jarl ES Wikberg ◽  
Lembit Rägo
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Male Rats ◽  
Receptor Antagonists ◽  
Y1 Receptor ◽  
Npy Receptor ◽  
Inhibit Food Intake ◽  
In Vitro Data

Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]- D-argininamide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304), and decapeptide [D-Tyr27,36D-Thr32]NPY27-36, after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr27,36D-Thr32]NPY27-36 was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.Key words: neuropeptide Y, NPY Y1 receptor antagonist, BIBO3304, BIBP3226, [D-Tyr27,36D-Thr32]NPY(27-36), 1229U91, food intake, MC4 receptor antagonist, HS014.

scholarly journals Evidence That the Inhibition of Luteinizing Hormone Secretion Exerted by Central Administration of Neuropeptide Y (NPY) in the Rat Is Predominantly Mediated by the NPY-Y5 Receptor Subtype1

Endocrinology ◽  
1999 ◽  
Vol 140 (9) ◽  
pp. 4046-4055 ◽  
Author(s):  
Paula D. Raposinho ◽  
Pierre Broqua ◽  
Dominique D. Pierroz ◽  
Amanda Hayward ◽  
Yvan Dumont ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Pancreatic Polypeptide ◽  
Inhibitory Action ◽  
Receptor Subtypes ◽  
Y1 Receptor ◽  
Npy Receptor ◽  
Gonadotropic Axis ◽  
Lh Secretion

Abstract A number of studies have indicated that neuropeptide Y (NPY) is a central regulator of the gonadotropic axis, and the Y1 receptor was initially suggested to be implicated. As at least five different NPY receptor subtypes have now been characterized, the aim of the present study was to reinvestigate the pharmacological profile of the receptor(s) mediating the inhibitory action of NPY on LH secretion by using a panel of NPY analogs with different selectivity toward the five NPY receptor subtypes. When given intracerebroventricularly (icv) to castrated rats, a bolus injection of native NPY (0.7–2.3 nmol) dose-dependently decreased plasma LH. Peptide YY (PYY; 2.3 nmol) was as potent as NPY, suggesting that the Y3 receptor is not implicated. Confirming previous data, the mixed Y1, Y4, and Y5 agonist[ Leu31,Pro34]NPY (0.7–2.3 nmol) inhibited LH release with potency and efficacy equal to those of NPY. Neither the selective Y2 agonist C2-NPY (2.3 nmol) nor the selective Y4 agonist rat pancreatic polypeptide affected plasma LH, excluding Y2 and Y4 subtypes for the action of NPY on LH secretion. The mixed Y4-Y5 agonist human pancreatic polypeptide (0.7–7 nmol) as well as the mixed Y2-Y5 agonist PYY3–36 (0.7–7 nmol) that displayed very low affinity for the Y1 receptor, thus practically representing selective Y5 agonists in this system, decreased plasma LH with potency and efficacy similar to those of NPY, indicating that the Y5 receptor is mainly involved in this inhibitory action of NPY on LH secretion.[ d-Trp32]NPY, a selective, but weak, Y5 agonist, also inhibited plasma LH at a dose of 7 nmol. Furthermore, the inhibitory action of NPY (0.7 nmol) on LH secretion could be fully prevented, in a dose-dependent manner (6–100 μg, icv), by a nonpeptidic Y5 receptor antagonist. This antagonist (60 μg, icv) also inhibited the stimulatory action of NPY (0.7 nmol) on food intake. The selectivity of PYY3–36, human PP,[ d-Trp32]NPY, and the Y5 antagonist for the Y5 receptor subtype was further confirmed by their ability to inhibit the specific[ 125I][Leu31,Pro34]PYY binding to rat brain membrane homogenates in the presence of the Y1 receptor antagonist BIBP3226, a binding assay system that was described as being highly specific for Y5-like receptors. With the exception of[ d-Trp32]NPY, all analogs able to inhibit LH secretion were also able to stimulate food intake. Taken together, these results indicate that the Y5 receptor is involved in the negative control by NPY of the gonadotropic axis.

scholarly journals A potent Neuropeptide Y (NPY) receptor antagonist 1229U91 suppresses spontaneous food intake in Zucker fatty rats

1997 ◽  
Vol 73 ◽  
pp. 180
Author(s):  
A. Ishihara ◽  
A. Kanatani ◽  
S. Asahi ◽  
T. Tanaka ◽  
M. Hidaka ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Npy Receptor

Central opioid receptors mediate glucoprivic inhibition of pituitary LH secretion

1997 ◽  
Vol 272 (4) ◽  
pp. E517-E522 ◽  
Author(s):  
K. P. Briski
Keyword(s):  
Receptor Antagonist ◽  
Opioid Receptor ◽  
Hormone Secretion ◽  
Male Rats ◽  
Pituitary Hormone ◽  
Intracerebroventricular Administration ◽  
Receptor Antagonists ◽  
Opioid Receptor Antagonist ◽  
Opioid Receptor Antagonists

The present studies investigated the significance of glucoprivic metabolic signals, particularly those of central origin, to the regulation of pituitary luteinizing hormone (LH). Groups of gonadectomized (GDX) adult male rats were treated with 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, by either intravenous (50, 100, or 200 mg/kg) or intracerebroventricular (5, 20, or 100 microg/rat) administration. Systemic drug treatment caused a significant decrease in mean plasma LH levels compared with saline-treated controls. Intracerebroventricular administration of 2-DG was also efficacious in suppressing circulating LH; animals treated with either of the two highest doses of the drug exhibited a significant reduction in plasma LH. In vitro studies examined direct effects of 2-DG on pituitary gonadotrope secretory activity. Exposure of anterior pituitary tissue to 2-DG during short-term perfusion had no significant impact upon either basal or gonadotropin-releasing hormone-stimulated LH release. Finally, groups of GDX rats were pretreated by intracerebroventricular administration of either the nonselective opioid receptor antagonist, naltrexone, or the selective mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA), before intravenous injection of 2-DG. Both receptor antagonists were observed to attenuate the suppressive effects of 2-DG on circulating LH in these animals. In summary, treatment of GDX rats with the glucose antimetabolite, 2-DG, decreased plasma LH, suggesting that metabolic signaling of cellular glucose oxidation is of physiological importance to the regulation of pituitary hormone secretion. Findings that plasma LH was diminished in animals treated intracerebroventricularly with 2-DG implicate central glucoprivic receptors in neuroendocrine mechanisms governing the reproductive endocrine axis. Attenuation of 2-DG-induced decreases in circulating LH by opioid receptor antagonists suggests that these receptors, particularly the mu-subtype, mediate central effects of glucoprivation on circulating LH.

Food intake regulation in rodents: Y5 or Y1 NPY receptors or both?

2000 ◽  
Vol 78 (2) ◽  
pp. 173-185 ◽  
Author(s):  
Jacques Duhault ◽  
Michèle Boulanger ◽  
Susana Chamorro ◽  
Jean A Boutin ◽  
Odile Della Zuana ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Inhibitory Effect ◽  
Receptor Subtype ◽  
Pharmacological Characterization ◽  
Npy Receptor ◽  
Obesity Drugs ◽  
Npy Receptors

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.Key words: obesity, weight reduction, food intake, neuropeptide Y, rodents.

scholarly journals Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake.

Endocrinology ◽  
1996 ◽  
Vol 137 (8) ◽  
pp. 3177-3182 ◽  
Author(s):  
A Kanatani ◽  
A Ishihara ◽  
S Asahi ◽  
T Tanaka ◽  
S Ozaki ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Y1 Receptor

Central Administration of BIBP3226, Neuropeptide Y (NPY) Y1 Receptor Antagonist, does not Inhibit Fasting- and NPY-Induced Food Intake in Neonatal Chicks

2001 ◽  
Vol 38 (4) ◽  
pp. 259-265 ◽  
Author(s):  
Shin-ichi Kawakami ◽  
Ryuichi Ando ◽  
Takashi Bungo ◽  
Atsushi Ohgushi ◽  
Tetsuya Tachibana ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Central Administration ◽  
Y1 Receptor ◽  
Neonatal Chicks

Regulation of food intake by neuropeptide Y in goldfish

2000 ◽  
Vol 279 (3) ◽  
pp. R1025-R1034 ◽  
Author(s):  
Yuwaraj K. Narnaware ◽  
Pierre P. Peyon ◽  
Xinwei Lin ◽  
Richard E. Peter
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Mrna Levels ◽  
Food Ration ◽  
Y1 Receptor ◽  
Daily Food ◽  
Daily Food Ration ◽  
Brain Ventricle ◽  
Dose Dependent Increase ◽  
Dose Dependent

In mammals, neuropeptide Y (NPY) is a potent orexigenic factor. In the present study, third brain ventricle (intracerebroventricular) injection of goldfish NPY (gNPY) caused a dose-dependent increase in food intake in goldfish, and intracerebroventricular administration of NPY Y1-receptor antagonist BIBP-3226 decreased food intake; the actions of gNPY were blocked by simultaneous injection of BIBP-3226. Goldfish maintained on a daily scheduled feeding regimen display an increase in NPY mRNA levels in the telencephalon-preoptic area and hypothalamus shortly before feeding; however, a decrease occured in optic tectum-thalamus. In both fed and unfed fish, brain NPY mRNA levels decreased after scheduled feeding. Restriction in daily food ration intake for 1 wk or food deprivation for 72 h resulted in increased brain NPY mRNA levels. Results from these studies demonstrate that NPY is a physiological brain signal involved in feeding behavior in goldfish, mediating its effects, at least in part, through Y1-like receptors in the brain.

scholarly journals Role of α1-adrenergic receptor subtypes in contractility of the rabbit abdominal aorta in vitro

2013 ◽  
Vol 82 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Jan Gnus ◽  
Albert Czerski ◽  
Stanisław Ferenc ◽  
Wojciech Zawadzki ◽  
Wojciech Witkiewicz ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Abdominal Aorta ◽  
Adrenergic Receptor ◽  
Receptor Subtypes ◽  
Organ Bath ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Selective Antagonists

Investigation of the effect of α1-adrenergic receptor subtypes on the contraction of the abdominal aorta will allow for more effective treatment of hypertension by use of selective antagonists. The aim of the study was to evaluate the participation of α1-adrenergic receptor subtypes in the contractility of the aortic smooth muscle cells in rabbits. The in vitro experiments were performed in isolated tissue preparations from 30 adult female New Zealand rabbits. The abdominal aortic sections were placed in organ bath chambers and contracted with increasing doses of non-selective α1-adrenergic receptor agonist phenylephrine without pre-incubation or after incubation in α1-adrenergic receptor subtype-selective or non-selective antagonists. Separate sections were incubated with increasing concentrations of antagonists. Phenylephrine caused maximal rise in arterial smooth muscle tone to 4.75 ± 0.47 mN. The most potent in blocking phenylephrine induced contraction was 5-metylurapidil (α1A-adrenergic receptor antagonist) followed by phentolamine and prazosin (non-selective α1-adrenergic receptor antagonists); BMY 7378 (α1D-adrenergic receptor antagonist), cyclazosin and L-765.314 (α1B-adrenergic receptor antagonists) were less effective. All antagonists, except BMY 7378 elicited relaxation of non-precontracted aorta in dose dependent manner. Our results indicate that postsynaptic α1A receptors are the most potent in producing rabbit abdominal aorta contraction, while α1B and α1D subtypes are less effective.

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