Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Abstract

In contrast, cyclo S±S [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y 2 -receptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y 1 -receptor, while binding to the Y 5 -receptor was affected less. Inhibition of cAMP-accumulation of selected peptides with replacements within position 20±23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligand±receptor interaction of NPY at the Y 1 -, Y 2 -and Y 5 -receptor and contribute to our understanding of subtype selectivity. Furthermore, the Y 1 -receptor-preferring peptides are novel tools that will provide insight into the physiological role of the Y 1 -receptor.Keywords: food intake; neuropeptides; NPY; selective ligands; structure±affinity relationship.Obesity, food intake and energy homeostasis are key areas of growing importance because obesity is beginning to replace malnutrition and infectious diseases as the most significant contributor to ill health in the developed world [1]. Neuropeptide Y (NPY) is one of the most important effector molecules of leptin: it is a key molecule in the regulation of food intake, it acts via several different receptor subtypes and elicits several physiological effects. Profound effects on stimulation of food intake, secretion of luteinizing and growth hormone, and insulin release suggest an important role for NPY in the pathophysiology of obesity and diabetes [2±5]. A wide range of other effects of NPY have been reported, such as potent vasoconstriction [6], facilitation of learning and memory [7], modulation of locomotor behaviours [8], induction of hypothermia [9,10], inhibition of sexual behaviour [11], shifts in circadian rhythms [12], modulation of cardiorespiratory parameters[13], anxiolytic potency [14] and inhibition of alcohol consumption and resistance [15].NPY is a 36-amino acid peptide amide belonging to the family of pancreatic polypeptides that includes also pancreatic polypeptide (PP) and peptide YY; it was first isolated from pig brain in 1982 [16].NPY is widely distributed within the central nervous system and in the periphery. [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27]. All receptors belong to the G-protein coupled receptor superfamily [28]. The correlation of a certain receptor subtype to a distinct physiological effect is not yet fully understood. Recent studies even suggest that different receptor subtypes redundantly mediate identical actions in a given system, as has been shown for the Y 1 -and Y 5 -receptor in the regulation of food intake [3]. Findings that deficiencies in either the Y 1 -or the Y 5 -receptors do not significantly impair the normal feeding response to fasting or NPY stimulation, strongly indicate that both Y receptors are involved in appetite regulation by NPY [29,30]. Selective receptor agonists or antagonists are useful tools with which to stu...

Neuropeptide Y (NPY) Suppresses Experimental Autoimmune Encephalomyelitis: NPY1 Receptor-Specific Inhibition of Autoreactive Th1 Responses In Vivo

“…Our study could be regarded as the first work to provide evidence that NPY modulates T cell function in vivo and that NPY is involved in the natural regulation of Th1-mediated autoimmunity. (24). Taking this into consideration, it is possible that stimulation of non-Y 1 receptors may compete with Y 1 receptor ligation.…”

Central nervous system neuropeptide Y signaling via the Y1 receptor partially dissociates feeding behavior from lipoprotein metabolism in lean rats

“…Recombinant NPY and a selective agonist for the Y2 receptor, human (h)PYY-(3-36), were purchased from GenScript (Piscataway, NJ). Selective agonists for the Y1 receptor, [F7, P34]-NPY, and the Y5 receptor, [Ala 31 , Aib 32 ]-NPY, were synthesized as described previously (13,58). A selective agonist for Y4, human PP (hPP), was purchased from Tocris Bioscience (Ellisville, MO).…”

“…All peptide ligands used in our studies are selective compounds for their respective NPY receptor subtypes and bind with subnanomolar affinity (35). The Y1 selective peptide [F7, P34]-NPY has Ͼ3,000-fold selectivity for the Y1 receptor over that of either the Y2 or Y5 receptor (58). For Y2 receptor activation, we used hPYY- , which has a 181-, Ͼ1,000-, and fivefold greater affinity for the Y2 receptor than for Y1, Y4, and Y5 receptor subtypes, respectively (69).…”

Appetite suppression based on selective inhibition of NPY receptors

“…147 The recent discovery of cyclo S-S [Cys 20 , Cys 24 ]pNPY -a highly selective ligand of the NPY Y 2 receptor may allow further study of the role of this subtype in the control of food intake (Table 4). 148 Knockout of the NPY Y 2 receptor. Knockout of the NPY Y 2 receptor produces an animal which is both hyperphagic and obese.…”

“…118 The first apparently selective NPY Y 1 receptor agonist was created by replacing both Ile 31 34 ]pNPY should prove very useful for further elucidating the effect of this receptor subtype in the control of food intake (Table 4). 148,153 Interestingly, when the affinity of modified NPY peptides for the NPY Y 1 receptor is compared with their ability to stimulate food intake after i.c.v. administration, a significant positive correlation emerges (Figure 3).…”