Potent and Selective 1,2,3-Trisubstituted Indole NPY Y-1 Antagonists

Hipskind, Philip A.; Lobb, Karen L.; Nixon, J. A.; Britton, Thomas C.; Bruns, Robert F.; Catlow, John T.; Dieckman-McGinty, D.; Gackenheimer, Susan L.; Gitter, Bruce D.; Iyengar, Smriti; Schober, Douglas A.; Simmons, Rosa Maria A.; Swanson, S. P.; Zarrinmayeh, Hamideh; Zimmerman, Dennis M.; Gehlert, Donald R.

doi:10.1021/jm970512x

Cited by 83 publications

(37 citation statements)

References 16 publications

(24 reference statements)

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“…Mice with both Y 1 or Y 5 receptor knockout gene exhibited mild obesity, although some differences were observed; the Y 1 receptor-deficient animal showed increased body weight without a change in food intake, mild hyperinsulemia, an elevated basal level of plasma insulin, and an absence of NPY-mediated vasoconstriction (43,44), whereas the Y 5 receptor-deficient mice presented hyperphagia (45). Inhibition of NPY-induced feeding was produced by both Y 1 and Y 5 receptor-selective nonpeptide antagonists (13,14,46,47 (Table II).…”

Section: Discussionmentioning

confidence: 98%

The First Selective Agonist for the Neuropeptide YY5Receptor Increases Food Intake in Rats

Cabrele¹,

Langer²,

Bader³

et al. 2000

Journal of Biological Chemistry

172

165

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Neuropeptide Y (NPY), 1 a 36-residue peptide amide, is a member of the pancreatic polypeptide (PP) hormone family that also includes PP and peptide YY (PYY) (1). NPY is expressed in the central and peripheral nervous systems and is one of the most abundant neuropeptides in the brain. Several important physiological activities, such as induction of food intake, inhibition of anxiety, increase in memory retention, presynaptic inhibition of neurotransmitter release, vasoconstriction, and regulation of ethanol consumption, have been attributed to NPY (2, 3). Especially, the role of NPY in feeding is of major interest because NPY receptor antagonists are potential anti-obesity drug candidates. Many studies have established the strong central influence of NPY in feeding behavior; for example, injection of NPY into the hypothalamus increases food intake (4, 5), and high NPY levels are correlated with leptin deficiency (6), the hormone that is secreted by adipocytes and regulates body weight and energy balance (7,8). Furthermore, NPY knockout can reduce obesity in leptin-deficient mice (named ob/ob mice) (6).Five distinct Y receptor subtypes that bind NPY, PYY, and PP with different affinities have been identified, cloned, and characterized (9). They all belong to the superfamily of the G-protein- Because highly specific tools to investigate the Y 5 receptor activity are still missing, we have focused our work on the design of NPY receptor agonists with both high affinity and selectivity for the Y 5 subtype. It is well established that the C-terminal part of NPY represents the interaction site with the Y receptors and that amino acid exchange is poorly tolerated in the region 33-36 (49); therefore, we induced a conformational change within the peptide region that mediates receptor binding by introducing the ␤-turn-inducing dipeptide Ala-Aib (aminoisobutyric acid) (19) into positions 31-32 of NPY and some peptides that contain segments of NPY and PP (NPY/PP chimeras). The [Ala 31 ,Aib 32 ]-modified peptides showed high selectivity for the Y 5 receptor. Furthermore, in vitro and in vivo studies clearly proved their NPY receptor agonism as well as stimulation of food intake.

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Section: Discussionmentioning

confidence: 98%

The First Selective Agonist for the Neuropeptide YY5Receptor Increases Food Intake in Rats

Cabrele¹,

Langer²,

Bader³

et al. 2000

Journal of Biological Chemistry

172

165

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“…Nevertheless, Y1-R Ϫ/Ϫ mice demonstrate a significantly blunted feeding response to fasting (Pedrazzini et al, 1998). Y1-R-selective antagonists (Kanatani et al, 1996;Hipskind et al, 1997;Kask et al, 1998) and antisense oligodeoxynucleotides for the Y1-R (Lopez-Valpuesta et al, 1996) inhibit food intake when administered centrally. In addition, when NPY-null mice are crossed with ob/ob mice, the obese phenotype is partially corrected (Erickson et al, 1996b).…”

Section: Functional Implicationsmentioning

confidence: 99%

Neuropeptide Y Y1 receptor mRNA in rodent brain: Distribution and colocalization with melanocortin-4 receptor

et al. 2004

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The central neuropeptide Y (NPY) Y1 receptor (Y1-R) system has been implicated in feeding, endocrine, and autonomic regulation. In the present study, we systematically examined the brain distribution of Y1-R mRNA in rodents by using radioisotopic in situ hybridization histochemistry (ISHH) with a novel sensitive cRNA probe. Within the rat hypothalamus, Y1-R-specific hybridization was observed in the anteroventral periventricular, ventromedial preoptic, suprachiasmatic, paraventricular (PVH), dorsomedial, ventromedial, arcuate, and mamillary nuclei. In the rat, Y1-R mRNA expression was also seen in the subfornical organ, anterior hypothalamic area, dorsal hypothalamic area, and in the lateral hypothalamic area. In addition, Y1-R hybridization was evident in several extrahypothalamic forebrain and hindbrain sites involved in feeding and/or autonomic regulation in the rat. A similar distribution pattern of Y1-R mRNA was observed in the mouse brain. Moreover, by using a transgenic mouse line expressing green fluorescent protein under the control of the melanocortin-4 receptor (MC4-R) promoter, we observed Y1-R mRNA expression in MC4-R-positive cells in several brain sites such as the PVH and central nucleus of the amygdala. Additionally, dual-label ISHH demonstrated that hypophysiotropic PVH cells coexpress Y1-R and pro-thyrotropin-releasing hormone mRNAs in the rat. These observations are consistent with the proposed roles of the central NPY/Y1-R system in energy homeostasis.

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“…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%

“…Starting from the compound LY357897 [72], the possibility of replacing the indole core with a benzimidazole core was investigated and structureaffinity and structure -activity relationship studies were carried out on a series of trisubstituted benzimidazoles [83]. The results suggest that at least two basic amine functionalities are required for high affinity, which may mimic the two Arg residues at positions 33 and 35 of NPY.…”

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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Potent and Selective 1,2,3-Trisubstituted Indole NPY Y-1 Antagonists

Cited by 83 publications

References 16 publications

The First Selective Agonist for the Neuropeptide YY5Receptor Increases Food Intake in Rats

The First Selective Agonist for the Neuropeptide YY5Receptor Increases Food Intake in Rats

Neuropeptide Y Y1 receptor mRNA in rodent brain: Distribution and colocalization with melanocortin-4 receptor

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

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