SR120819A, an orally‐active and selective neuropeptide Y Y1 receptor antagonist

Gal, Claudine Serradeil–Le; Valette, G; Rouby, Pierre-Eric; Pellet, Alain; Oury-Donat, Florence; Brossard, Gabrielle; Lespy, Liliane; Marty, E.; Néliat, Gervais; Cointet, P. De; Maffrand, Jean‐Pierre; Fur, G. Le

doi:10.1016/0014-5793(95)00230-7

Cited by 109 publications

(53 citation statements)

References 20 publications

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“…The relatively short duration of action (within 2 h) and the lack of oral bioavailability represent two limitations of BIBP3226. The first orally-active Y 1 -receptor selective antagonist, known as SR120819A, showed a K i value of 15 nM [70]. Two further more potent antagonists have recently been developed, which are characterized by a subnanomolar affinity: BIBO3304 (IC 50 0.38 nM), an analog of BIBP3226 where the hydroxy group has been replaced with the methylurea moiety [71], and LY357897 (K i 0.75 nM), a trisubstituted indole [72].…”

Section: Antagonistsmentioning

confidence: 99%

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

2000

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Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to the NPY hormone family and activate a class of receptors called the Y-receptors, and also belong to the large superfamily of the G-protein coupled receptors. Structure-affinity and structure-activity relationship studies of peptide analogs, combined with studies based on site-directed mutagenesis and anti-receptor antibodies, have given insight into the individual characterization of each receptor subtype relative to its interaction with the ligand, as well as to its biological function. A number of selective antagonists at the Y1-receptor are available whose structures resemble that of the C-terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in vivo investigations of the NPY-induced increase in food intake. Y2-receptor selective agonists are the analog cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY and the TASP molecule containing two units of the NPY segment 21-36. Now the first antagonist with nanomolar affinity for the Y2-receptor is also known, BIIE0246. So far, the native peptide PP has been shown to be the most potent ligand at the Y4-receptor. However, by the design of PP/NPY chimera, some analogs have been found that bind not only to the Y4-, but also to the Y5-receptor with subnanomolar affinities, and are as potent as NPY at the Y1-receptor. For the characterization of the Y5-receptor in vitro and in vivo, a new class of highly selective agonists is now available. This consists of analogs of NPY and of PP/NPY chimera which all contain the motif Ala31-Aib32. This motif has been shown to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be the key motif for high Y5-receptor selectivity. The results of feeding experiments in rats treated with the first highly specific Y5-receptor agonists support the hypothesis that this receptor plays a role in the NPY-induced stimulation of food intake. In conclusion, the selective compounds for the different Y receptor subtypes known so far are promising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors.

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Section: Antagonistsmentioning

confidence: 99%

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

2000

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“…Moreover, Y1, but not Y5, antagonists block the effects of NPY on food intake in rats (30), and fasting-induced food intake was reduced in Y1 but not Y5 knockout mice (38). Also, NPY-Y1 receptors are abundant in the ARC and PVN (32,48,62). Our results indicate a role for NPY-Y1R in regulating NPY's effects on ␣-MSH, as blocking these receptors restored the NPY-induced decrease in both PC2 levels and ␣-MSH release.…”

Section: E647 Npy Regulates Pomc Processingmentioning

confidence: 99%

Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

Cyr

Toorie

Steger

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Cyr NE, Toorie AM, Steger JS, Sochat MM, Hyner S, Perello M, Stuart R, Nillni EA. Mechanisms by which the orexigen NPY regulates anorexigenic ␣-MSH and TRH. Am J Physiol Endocrinol Metab 67: E640 -E650, 2013. First published January 15, 2013; doi:10.1152/ajpendo.00448.2012.-Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic ␣-melanocyte-stimulating hormone (␣-MSH) and thyrotropin-releasing hormone (TRH) peptides produced in the hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, respectively. Neuropeptide Y (NPY) promotes positive energy balance in part by suppressing ␣-MSH and TRH. The mechanism by which NPY regulates ␣-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of ␣-MSH's inactive precursor proopiomelanocortin (POMC) by decreasing the prohormone convertase-2 (PC2). We also found that early growth response protein-1 (Egr-1) and NPY-Y1 receptors mediated the NPY-induced decrease in PC2. NPY given intra-PVN also decreased PC2 in PVN samples, suggesting a reduction in PC2-mediated pro-TRH processing. In addition, NPY attenuated the ␣-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased ␣-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of ␣-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and ␣-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.␣-melanocyte-stimulating hormone; early growth response protein-1; neuropeptide Y; proopiomelanocortin; thyrotropin-releasing hormone OBESITY IS A MAJOR HEALTH and socioeconomic concern that has reached epidemic proportions in developed nations. Despite efforts to abate the problem, cases of obesity continue to rise. Thus, it is imperative to better understand the physiological mechanisms controlling food intake and body weight.Neuropeptide Y (NPY) is a potent orexigen that has received attention as an antiobesity drug target (69). NPY is produced both centrally and peripherally. Although it is widely distributed throughout the brain, in situ hybridization studies reveal that NPY is most densely localized to the hypothalamic arcuate nucleus (ARC) (19,41). Hypothalamic NPY plays an important role in energy balance and responds to changes in energy status. For example, NPY increases during food deprivation and returns to baseline levels following refeeding in the hypothalamic ARC and paraventricular nucleus (PVN) (1, 2, 29).Hypothalamic NPY also responds to changes in energy status signals, as it decreases with elevated leptin or insulin levels and increases with elevated ghrelin, growth hormone, or glucocorticoid levels (69). In addition, rodent models of genetic obesity including the fa/fa Zucker rat as well as db/db and ob/ob mice demonstrate increased hypothalamic...

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“…9). Two additional Y 1 antagonists are J-115814 (structure 20; K i for human Y 1 ¼ 1.5 nM) [295] and the first orally active antagonist SR120819A (structure 21; K i for human Y 1 ¼ 15 nM) [296]. Interestingly, the peptidic Y 1 antagonist, GR231118 (structure 22) was also shown to be an agonist at the Y 4 receptor [297,298].…”

Section: Biological Actions and Receptor Pharmacologymentioning

confidence: 99%

Endogenous Vasoactive Peptides

Webb

Ksander²

2010

Burger's Medicinal Chemistry and Drug Discovery

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The control of vasomotor tone regulates the overall cardiovascular system and its responses to physiological and pathophysiological stress. It provides differential blood flow to regional vascular beds under normal physiologic conditions, at times of normal stress, such as exercise, and during conditions of pathological stress, such as congestive heart failure. Although the vascular system regulates many of its functions at the site of the blood vessel itself, other factors that may control vascular tone include the autonomic nervous system, circulating hormones functioning in an endocrine role, and reflex metabolic control. Many newly discovered peptides were found to be widespread in autonomic and sensory neurons innervating the vasculature, and they possess potent vasoactive effects on many blood vessels. Vasoactive peptides have been shown to play an important role in many pathological situations, for example, asthma, arthritis, vascular headaches, hypertension, and other cardiovascular diseases. In this chapter, we will outline the evidence for the different actions of various vasoactive peptides, their interaction with other systems, the possible role they have in diseases, and the present and future therapeutic use of vasoactive peptide agonists and antagonists.

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SR120819A, an orally‐active and selective neuropeptide Y Y1 receptor antagonist

Cited by 109 publications

References 20 publications

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

Endogenous Vasoactive Peptides

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