Pharmacological characterization and selectivity of the NPY antagonist GR231118 (1229U91) for different NPY receptors

Matthews, James L.; Jansen, Marilyn; Lyerly, Donald; Cox, Richard F.; Chen, Wenji; Koller, Kerry J.; Daniels, Alejandro J.

doi:10.1016/s0167-0115(97)01044-6

Cited by 45 publications

(24 citation statements)

References 19 publications

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“…The first speculations on homodimerization of NPY receptors come from studies on the hY 1 -receptor antagonist GR231118 (42) 36, which bind as dimers with a higher affinity to the hY 1 -receptor than as monomer. We assumed that homodimerization of the hY 1 -receptor could be the reason for the higher affinity.…”

Section: Discussionmentioning

confidence: 99%

“…NPY modulates numerous physiological processes including regulation of cardiovascular (38) and renal functions, intestinal motility, memory (39), anxiety, seizures, feeding (40), circadian rhythm (41), and nociception. First speculations for homodimerization come from studies with recently reported truncated NPY analogues named ([P 30 ,C 31 (42,43) that bind after dimerization with a higher affinity to the hY 1 -receptor. Furthermore, the homodimeric, peptidergic GR231118 (Y 1 -antagonist, Y 4 agonist) obtains a higher affinity for the Y 1 -receptor than its monomeric form (42,43).…”

Section: G-protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

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Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Dinger¹,

Bader²,

Kóbor³

et al. 2003

Journal of Biological Chemistry

120

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Up to now neuropeptide Y (NPY) receptors, which belong to the large family of G-protein-coupled receptors and are involved in a broad range of physiological processes, are believed to act as monomers. Studies with the Y 1 -receptor antagonist and Y 4 -receptor agonist GR231118, which binds with a 250-fold higher affinity than its monomer, led to the first speculation that NPY receptors can form homodimers. In the present work we used the fluorescence resonance energy transfer (FRET) to study homodimerization of the hY 1 -, hY 2 -, and hY 5 -receptors in living cells. For this purpose, we generated fusion proteins of NPY receptors and green fluorescent protein or spectral variants of green fluorescent protein (cyan, yellow, and red fluorescent protein), which can be used as FRET pairs. Two different FRET techniques, fluorescence microscopy and fluorescence spectroscopy, were applied. Both techniques clearly showed that the hY 1 -, hY 2 -, and hY 5 -NPY receptor subtypes are able to form homodimers. By using transiently transfected cells, as well as a stable cell line expressing the hY 2 -GFP fusion protein, we could demonstrate that the Y-GFP fusion proteins are still functional and that dimerization varies from 26 to 44% dependent on the receptor. However, homodimerization is influenced neither by NPY nor by G␣ protein binding. G-protein-coupled receptors (GPCRs)1 represent a superfamily of proteins characterized by seven transmembrane ␣-helices that interact with a family of heterotrimeric GTP-binding proteins, referred to as G-proteins (1). GPCRs are found in a wide range of organisms, and many kind of chemical messengers act through them, for example adrenalin, angiotensin, or neuropeptide Y (NPY). Ligands for GPCRs are involved in a broad range of physiological functions, and their malfunction is responsible for many diseases (2, 3).Until recently GPCRs were thought to function as monomers. However, a growing number of evidence suggests that they may exist as homodimers and heterodimers (4 -9). The existence of homodimers has been shown for several GPCRs including ␤ 2 -adrenergic receptor (10 -12), ␦-and -opioid receptors (6, 13), metabotropic glutamate receptor 5 (14), calcium-sensing receptor (15-17), m3 muscarinic receptor (18, 19), vasopressin V2-receptor (20), somatostatin (21, 22), and dopamine receptors (23)(24)(25). Whereas homodimerization of the somatostatin receptor 5 (21), the ␦-opioid receptor (13), and the ␤ 2 -adrenergic receptor (11) are agonist-mediated, dimerization of the -opioid receptor (26) is agonistindependent.So far photoaffinity labeling (27), cross-linking studies (15, 24), Western blot analysis (14), and immunoprecipitation (17,28,29) are the most frequently applied methods for the investigation of receptor homodimerization. Because of the development of new fluorescent dyes, novel fluorescent proteins, and new instrumentation, the fluorescence resonance energy transfer (FRET) obtained a renaissance (30) and could be applied recently for the investigation of receptor dimerization...

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Section: Discussionmentioning

confidence: 99%

Section: G-protein-coupled Receptors (Gpcrs)mentioning

confidence: 99%

Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Dinger¹,

Bader²,

Kóbor³

et al. 2003

Journal of Biological Chemistry

120

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“…Experimental design. The study consisted of six experiments in two series of three experiments each: the first three (experiments 1, 2, and 3) used 1229U91, and the second three (experiments 4, 5, and 6) used D-Tyr 27,36 , D-Thr 32 NPY [27][28][29][30][31][32][33][34][35][36] . The initial experiment in each series (experiments 1 and 4) consisted of two groups of rats, one with third intracerebroventricular cannulas (experiment 1a, n ϭ 10; experiment 4a, n ϭ 7) and one with fourth intracerebroventricular cannulas (experiment 1b, n ϭ 13; experiment 4b, n ϭ 7).…”

Section: Methodsmentioning

confidence: 99%

“…The first, 1229U91, is a well-characterized and relatively selective NPY-Y1 receptor antagonist (34) with some agonist activity at the NPY-Y4 receptor (35 (36), is a COOH-terminal NPY fragment with contrasting subtype selectivity; available evidence suggests that it is unlikely to bind to the Y1 receptor (37). The two antagonists were similarly effective at reversing ghrelin hyperphagia in "open-ventricle" experiments but differentially potent in aqueduct occlusion experiments, depending on site of administration.…”

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confidence: 99%

Distinct Forebrain and Caudal Brainstem Contributions to the Neuropeptide Y Mediation of Ghrelin Hyperphagia

2005

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G hrelin, the endogenous ligand for the growth hormone secretagogue (GHS) receptor (1), induces a hyperphagic response when delivered centrally (2-6). GHS receptors are located on neuropeptide Y (NPY)/agouti-related protein neurons in the arcuate nucleus of the hypothalamus (ARC) (7), and it is generally held that projections from these neurons to those in the paraventricular nucleus (PVN) and perhaps in other hypothalamic regions are an essential link in the downstream mediation of the orexigenic actions of ghrelin (8,9). Consistent with this view is evidence showing that ghrelin induces c-fos expression (5,10 -12) and NPY mRNA expression in ARC (10,13,14) and stimulates electrophysiological activity in NPY/agouti-related protein neurons (8,15). Central administration of either ghrelin or NPY also activates c-fos expression in the PVN (16 -18), an area with strong expression of NPY-Y1 and Y5 receptors (19). Functional support for the mediation of ghrelin hyperphagia by NPY systems comes from pharmacological studies in which NPY antibodies (14) or receptor antagonists (3,5,20,21) were shown to abolish ghrelin-induced feeding. The results of these studies, in which ligands were delivered to forebrain ventricles, are consistent with the view that the relevant GHS and NPY receptors are contained within the hypothalamus.The anatomical extent of the substrates supporting the ghrelin-NPY interaction relevant to feeding control, however, remains open to question. Attribution of a hypothalamic site of action for the pharmacological studies is tenuous, given that the caudal flow of cerebrospinal fluid (CSF) through the ventricular system carries ligands to behaviorally potent receptor populations in the caudal brainstem (CBS). Thus, with ghrelin and the NPY receptor antagonist both delivered to the third or lateral ventricles (20,21), it is possible that CBS receptors and circuits contribute to either or both the primary ghrelin effect and its reversal. GHS receptors are clearly represented in the CBS (22,23), as are the NPY receptor subtypes most commonly implicated in the control of ingestive behavior (24 -27). Targeted stimulation of brainstem GHS receptors (6) or NPY receptors (28,29), moreover, yields robust hyperphagic responses at low doses. Furthermore, as shown below, delivery of NPY antagonists to the fourth (hindbrain) ventricle completely reverses the hyperphagic response observed when ghrelin is administered through the same cannula. The parity of the results derived from

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“…For example, [Nle 30 ]hPP [25][26][27][28][29][30][31][32][33][34][35][36] and [Leu 34 ]pNPY [25][26][27][28][29][30][31][32][33][34][35][36] were found to be Y 4 R selective partial agonists, 10 and a nonapeptide based on the C-terminal fragment of NPY, Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg- [28][29][30][31][32][33][34][35][36] ], also known as 1229U91, showed enhanced potency at both receptor subtypes but is in particular the most potent known Y 1 R antagonist. [13][14][15][16][17] Another of several highly potent Y receptor ligands based upon dimeric C-terminal sequences is D/L-2,7-diaminooctanedioyl-bis(YRLRY-NH 2 ), 1 (BVD-74D) 18 ( Figure 1). …”

Section: Introductionmentioning

confidence: 99%

Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y₄ Receptor Agonist Derived by an Olefin Metathesis Approach

et al. 2016

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(2016) Optically pure, structural and fluorescent analogues of a dimeric Y4 receptor agonist derived by an olefin metathesis approach. Journal of Medicinal Chemistry . ISSN 1520-4804 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/34144/1/acs.jmedchem.6b00310.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: http://eprints.nottingham.ac.uk/end_user_agreement.pdf A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.uk Just Accepted "Just Accepted" manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides "Just Accepted" as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. "Just Accepted" manuscripts appear in full in PDF format accompanied by an HTML abstract. "Just Accepted" manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). "Just Accepted" is an optional service offered to authors. Therefore, the "Just Accepted" Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the "Just Accepted" Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these "Just Accepted" manuscripts. 1Optically pure, structural and fluorescent analogues of a dimeric Y 4 receptor agonist derived by an olefin metathesis approach. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59

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Pharmacological characterization and selectivity of the NPY antagonist GR231118 (1229U91) for different NPY receptors

Cited by 45 publications

References 19 publications

Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Distinct Forebrain and Caudal Brainstem Contributions to the Neuropeptide Y Mediation of Ghrelin Hyperphagia

Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y₄ Receptor Agonist Derived by an Olefin Metathesis Approach

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Pharmacological characterization and selectivity of the NPY antagonist GR231118 (1229U91) for different NPY receptors

Cited by 45 publications

References 19 publications

Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Homodimerization of Neuropeptide Y Receptors Investigated by Fluorescence Resonance Energy Transfer in Living Cells

Distinct Forebrain and Caudal Brainstem Contributions to the Neuropeptide Y Mediation of Ghrelin Hyperphagia

Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y4 Receptor Agonist Derived by an Olefin Metathesis Approach

Contact Info

Product

Resources

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Optically Pure, Structural, and Fluorescent Analogues of a Dimeric Y₄ Receptor Agonist Derived by an Olefin Metathesis Approach