Ž . European Journal of Pharmacology 349 1998 97–105 ž / GR231118 1229U91 and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y receptor antagonists and 1 neuropeptide Y Y receptor agonists 4 Eric M. Parker a, ) , Carol K. Babij a , Ambikaipakan Balasubramaniam b , Robert E. Burrier a,1 , Mario Guzzi a , Fozia Hamud a , Gitali Mukhopadhyay a , Mark S. Rudinski a , Z. Tao b , Melissa Tice a , Ling Xia a , Deborra E. Mullins a , Brian G. Salisbury a a Department of Central NerÕous System and CardioÕascular Research, Schering-Plough Research Institute, Mail Stop K-15-3-3600, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA b DiÕision of Gastrointestinal Hormones, Department of Surgery, UniÕersity of Cincinnati Medical Center, Cincinnati, OH 45267, USA Received 11 December 1997; revised 17 February 1998; accepted 24 February 1998 Abstract Ž X .w 31 32 34 x Ž .4 Ž . w x GR231118, BW1911U90, Bis 31r31 Cys , Trp , Nva neuropeptide Y 31–36 T-190 and Trp–Arg–Nva–Arg–Tyr -NH 2 2 Ž . T-241 are peptide analogs of the C-terminus of neuropeptide Y that have recently been shown to be antagonists of the neuropeptide Y Y receptor. In this study, the activity of these peptides at each of the cloned neuropeptide Y receptor subtypes is determined in 1 Ž . radioligand binding assays and in functional assays inhibition of forskolin-stimulated cAMP formation . GR231118 is a potent antagonist Ž . at the human and rat neuropeptide Y Y receptors p A s10.5 and 10.0, respectively; p K s10.2 and 10.4, respectively , a potent 1 2 i Ž . agonist at the human neuropeptide Y Y receptor pEC s8.6; p K s9.6 and a weak agonist at the human and rat neuropeptide Y Y 4 50 i 2 Ž . and Y receptors. GR231118 also has high affinity for the mouse neuropeptide Y Y receptor p K s8.8 . Therefore, GR231118 is a 5 6 i relatively selective neuropeptide Y Y receptor antagonist, but has appreciable activity at the neuropeptide Y Y and Y receptors as well. 1 4 6 Ž BW1911U90, T-190 and T-241 are moderately potent neuropeptide Y Y receptor antagonists p A s7.1, 5.8 and 6.5, respectively; 1 2 . Ž p K s8.3, 6.5 and 6.8, respectively and neuropeptide Y Y receptor agonists pEC s6.8, 6.3 and 6.6, respectively; p K ;8.3, 7.7 and i 4 50 i . 8.3, respectively . These data suggest that the C-terminus of neuropeptide Y and related peptides is sufficient for activation of the neuropeptide Y Y receptor, but is not sufficient for activation of the neuropeptide Y Y receptor. Because BW1911U90, T-190 and 4 1 T-241 are significantly less potent at the cloned human neuropeptide Y Y receptor than at the neuropeptide Y receptor in human 1 erythroleukemia cells, these cells may express a novel neuropeptide Y receptor with high affinity for these peptides. q 1998 Elsevier Science B.V. All rights reserved. Keywords: Neuropeptide Y; GW1229; 1229U91; GR 231118; Neuropeptide Y receptor 1. Introduction Neuropeptide Y is a 36 amino acid neuropeptide that is widely distributed in the central and peripheral nervous Ž . systems Wahlestedt and Reis, 1993 . As might be ex- pected from its wide distribution, neuropeptide Y has a plethora of physiological effects. In the central nervous system, neuropeptide Y stimulates food intake, decreases thermogenesis, modulates pituitary hormone secretion and ) Corresponding author. Tel.: q1-908-298-7389; fax: q1-908-298- 2383; e-mail: eric.parker@spcorp.com 1 Present Address: Lead Generation Biology, Sphinx Pharmaceuticals, 4615 University Drive, Durham, NC 27707, USA. Ž has anxiolytic and anti-convulsant activity Turton et al., . 1997; Woldbye et al., 1997 . In the periphery, neuropep- tide Y has been shown to regulate vascular tone and to contract or relax smooth muscle in a variety of tissues Ž . Wahlestedt et al., 1990; Malmstrom and Lundberg, 1997 . The multiple physiological effects of neuropeptide Y are mediated by at least six different G protein-coupled recep- Ž tors designated Y , Y , Y , Y , Y and Y Michel et al., 1 2 3 4 5 6 . 1998 . With the exception of the neuropeptide Y Y recep- 3 tor, each of these neuropeptide Y receptors has been cloned. There may also be additional neuropeptide Y receptors that have not yet been identified by molecular Ž . cloning Michel et al., 1998 . Unequivocal determination of the neuropeptide Y receptors that mediate the various 0014-2999r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved.