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

Abstract

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.

Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea‐pig

“…Another approach to study the contribution of Y 1 and Y 5 receptors to food intake regulation is to develop highly subtype selective agonists for the NPY receptors. Such compounds have been described for the Y 1 and Y 5 receptors (Cabrele et al, 2000;SoÈ ll et al, 2001) and their in vivo e ects in guinea-pigs are under investigation in our laboratory.…”

Receptor Subtype-specific Docking of Asp6.59 with C-terminal Arginine Residues in Y Receptor Ligands

“…However, the C-terminal pentapeptide of all natural ligands was identified as an essential region for binding to all YRs (23,24), and these residues of the ligand C terminus seem to represent a core contact domain. Interestingly, studies of analogs containing conformational constraints, when bound at the various YR subtypes, support the concept of structural differences between subtypes in this domain (25)(26)(27)(28). However, the two conserved Arg residues at positions 33 and 35 are important contact sites for all YRs.…”

The NPY/AgRP neuron and energy homeostasis

“…NPY Y5 receptor antagonists also inhibit food intake, but surprisingly have no effect on NPY-induced feeding responses, 38 raising questions about the role of Y5 in NPY's feeding effects. However, NPY Y5 receptor selective agonists stimulate feeding 39,40 and NPY Y5-deficient mice do have blunted feeding in response to NPY. 41 Taken together, these data suggest a role for both Y1 and Y5 receptors in the orexigenic actions of NPY.…”