Y-receptor affinity modulation by the design of pancreatic polypeptide/neuropeptide Y chimera led to Y5-receptor ligands with picomolar affinity

Cabrele, Chiara; Wieland, H.; Langer, Michael; Stidsen, Carsten E.; Beck‐Sickinger, Annette G.

doi:10.1016/s0196-9781(01)00339-4

Cited by 38 publications

(21 citation statements)

References 19 publications

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“…All three radioligands bind to the Y 5 receptor subtype, although with different affinities (Michel et al, 1998;Dumont et al, 2004a (Cabrele et al, 2001); and nonpeptide Y 5 antagonists, such as CGP71683A (Criscione et al, 1998), JCF109 (Feletou et al, 1999), CP732925 (Elliott et al, 2003), and CP760542 and CP781214 (Yannielli et al, 2004). As shown in Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The Leu 31 Pro 34 -substituted analogs of NPY and PYY are also potent agonists on the Y 4 subtype (Gehlert et al, 1996). This receptor subtype can be activated by PYY and NPY, but with much lower potencies than the PPs (Lundell et al, 1995 , and hPP display potent agonist activities, whereas NPY(13-36), PYY(13-36), rPP, and GR231118 are much less active (Michel et al, 1998;Dumont et al, 2004a (Cabrele et al, 2001). In addition, various nonpeptide Y 5 antagonists have been characterized including CGP71683A (Criscione et al, 1998), JCF109 (Feletou et al, 1999), CP732925 (Elliott et al, 2003), and CP760542 and CP781214 (Yannielli et al, 2004 (Dumont et al, 1998) and the finding that BIBO3304 (Y 1 antagonist) and CGP71683A (Y 5 antagonist) were able to compete for 75 and 25% of specific ,Pro 34 ]hPYY binding, respectively (Dumont et al, 2000a).…”

Section: Resultsmentioning

confidence: 99%

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Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in Rat Brain

Dumont

Moyse²,

Fournier³

et al. 2005

J Pharmacol Exp Ther

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in Rat Brain

Dumont

Moyse²,

Fournier³

et al. 2005

J Pharmacol Exp Ther

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“…As shown in Table II and Fig. 1 (50). The PP/NPY chimeras were modified by the introduction of the Ala-Aib dipeptide at positions 31-32.…”

Section: Resultsmentioning

confidence: 99%

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

Cabrele¹,

Langer²,

Bader³

et al. 2000

Journal of Biological Chemistry

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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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“…This helicity could reduce sidechain mobility and availability, and then also the potential for low-affinity binding. The 19–23 tract of Y peptides contributes to specific binding [9], structuring [28] and receptor selectivity [8], but the difference between hNPY and hPYY or pPYY is only in the conservative switch of A and S at 22–23, and the following heptads are identical (Table 4). The 24–30 sector, LRHY[I,L]NL, differs only at position 28, and conservatively, for hNPY and hPYY or pPYY (Table 4).…”

Section: Resultsmentioning

confidence: 99%

Non-specific binding and general cross-reactivity of Y receptor agonists are correlated and should importantly depend on their acidic sectors

et al. 2011

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Non-specific binding of Y receptor agonists to intact CHO cells, and to CHO cell or rat brain particulates, is much greater for human neuropeptide Y (hNPY) compared to porcine peptide Y (pPYY), and especially relative to human pancreatic polypeptide (hPP). This binding of hNPY is reduced by alkali cations in preference to non-ionic chaotrope urea, while the much lower non-specific binding of pPYY is more sensitive to urea. The difference could mainly be due to the 10–16 stretch in 36-residue Y agonists (residues 8–14 in N-terminally clipped 34-peptides), located in the sector that contains all acidic residues of physiological Y agonists. Anionic pairs containing aspartate in the 10–16 zone could be principally responsible for non-specific attachments, but may also aid the receptor site binding. Two such pairs are found in hNPY, one in pPYY, and none in hPP. The hydroxyl amino acid residue at position 13 in mammalian PYY and PP molecules could lower conformational plasticity and the non-selective binding via intrachain hydrogen bonding. The acidity of this tract could also be important in agonist selectivity of the Y receptor subtypes. The differences point to an evolutionary reduction of promiscuous protein binding from NPY to PP, and should also be important for Y agonist selectivity within NPY receptor group, and correlate with partial agonism and out-of group cross-reactivity with other receptors.

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Y-receptor affinity modulation by the design of pancreatic polypeptide/neuropeptide Y chimera led to Y5-receptor ligands with picomolar affinity

Cited by 38 publications

References 19 publications

Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in Rat Brain

Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in Rat Brain

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

Non-specific binding and general cross-reactivity of Y receptor agonists are correlated and should importantly depend on their acidic sectors

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