[D-Trp 34 ] neuropeptide Y is a potent and selective neuropeptide Y Y 5 receptor agonist with dramatic effects on food intake Eric M. Parker a, *, Ambikaipakan Balasubramaniam b , Mario Guzzi a , Deborra E. Mullins a , Brian G. Salisbury a , Sulaiman Sheriff b , Melanie B. Witten a , Joyce J. Hwa a a Department of CNS and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA b Division of Gastrointestinal Hormones, Department of Surgery, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA Received 13 August 1999; accepted 23 December 1999 Abstract The neuropeptide Y (NPY) Y 5 receptor has been proposed to mediate several physiological effects of NPY, including the potent orexigenic activity of the peptide. However, the lack of selective NPY Y 5 receptor ligands limits the characterization of the physiological roles of this receptor. Screening of several analogs of NPY revealed that [D-Trp 34 ]NPY is a potent and selective NPY Y 5 receptor agonist. Unlike the prototype selective NPY Y 5 receptor agonist [D-Trp 32 ]NPY, [D-Trp 34 ]NPY markedly increases food intake in rats, an effect that is blocked by the selective NPY Y 5 receptor antagonist CGP 71683A. These data demonstrate that [D-Trp 34 ]NPY is a useful tool for studies aimed at determining the physiological roles of the NPY Y 5 receptor. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Neuropeptide Y; Neuropeptide Y receptor; Y 5 receptor; [D-Trp 34 ]NPY; [D-Trp 32 ]NPY; Food intake 1. Introduction Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the mammalian nervous system and has been associated with a wide variety of physiological effects [7,21]. NPY elicits its manifold biologic effects by interact- ing with at least six different G protein-coupled receptors known as Y 1 ,Y 2 ,Y 3 ,Y 4 ,Y 5 , and y 6 [7,15]. Although each NPY receptor subtype has a unique pharmacological profile that can be defined with peptide analogs of NPY, peptide and nonpeptide ligands that bind to each receptor subtype with high potency and selectivity are only beginning to emerge [1,4,5,8,11,19,24,25]. The development of addi- tional potent and selective agonists and antagonists of each of the NPY receptor subtypes will be critical in the quest to determine the physiological roles played by each receptor. The NPY Y 5 receptor is the most recently discovered NPY receptor and, hence, its biologic roles remain largely undefined [7,8]. The NPY Y 5 receptor has been proposed to mediate several physiological effects of NPY, including stimulation of feeding, anticonvulsant effects, diuresis, na- triuresis, calciuresis, inhibition of neuronal firing, contrac- tion of ileal smooth muscle, reduction of blood glucose, and attenuation of naloxone-precipitated opiate withdrawal [2,3, 8,10,17,22,23]. The association of the NPY Y 5 receptor with each of these physiological effects is based on a com- parison of the relative potencies of a series of peptides to elicit each physiological effect with the potencies of these peptides to bind to or activate the NPY Y 5 receptor. How- ever, most of these studies have not used agonists or antag- onists that are selective for the NPY Y 5 receptor and, hence, the association of the NPY Y 5 receptor with these physio- logical effects must remain tentative. A series of NPY analogs containing D-Trp substitutions at positions 32, 34, and 36 have previously been synthesized for the purpose of examining the structure-activity require- ments of the NPY receptor that mediates NPY-induced feeding [1]. D-Trp substitutions in the C-terminal region of NPY were chosen because this unnatural amino acid has been found to impart antagonist properties to other peptides (e.g. 9) and because substitutions in the C-terminus of NPY would be expected to cause dramatic changes in the binding  This work was supported by NIH grant GM47122 and by Schering– Plough Corporation. * Corresponding author. Tel.: +1-908-740-7389; fax: +1-908-740- 2383. E-mail address: eric.parker@spcorp.com (E.M. Parker). Peptides 21 (2000) 393–399 0196-9781/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0196-9781(00)00156-X