GR231118 (1229U91) and other analogues of the C-terminus of neuropeptide Y are potent neuropeptide Y Y1 receptor antagonists and neuropeptide Y Y4 receptor agonists.
GR231118, BW1911U90, Bis(31/31')[[Cys31, Trp32, Nva34] neuropeptide Y(31-36)] (T-190) and [Trp-Arg-Nva-Arg-Tyr]2-NH2 (T-241) are peptide analogs of the C-terminus of neuropeptide Y that have recently been shown to be antagonists of the neuropeptide Y Y1 receptor. In this study, the activity of these peptides at each of the cloned neuropeptide Y receptor subtypes is determined in radioligand binding assays and in functional assays (inhibition of forskolin-stimulated cAMP formation). GR231118 is a potent antagonist at the human and rat neuropeptide Y Y1 receptors (pA2 = 10.5 and 10.0, respectively; pKi = 10.2 and 10.4, respectively), a potent agonist at the human neuropeptide Y Y4 receptor (pEC50 = 8.6; pKi = 9.6) and a weak agonist at the human and rat neuropeptide Y Y2 and Y5 receptors. GR231118 also has high affinity for the mouse neuropeptide Y Y6 receptor (pKi = 8.8). Therefore, GR231118 is a relatively selective neuropeptide Y Y1 receptor antagonist, but has appreciable activity at the neuropeptide Y Y4 and Y6 receptors as well. BW1911U90, T-190 and T-241 are moderately potent neuropeptide Y Y1 receptor antagonists (pA2 = 7.1, 5.8 and 6.5, respectively; pKi = 8.3, 6.5 and 6.8, respectively) and neuropeptide Y Y4 receptor agonists (pEC50 = 6.8, 6.3 and 6.6, respectively; pKi; 8.3, 7.7 and 8.3, respectively). These data suggest that the C-terminus of neuropeptide Y and related peptides is sufficient for activation of the neuropeptide Y Y4 receptor, but is not sufficient for activation of the neuropeptide Y Y1 receptor. Because BW1911U90, T-190 and T-241 are significantly less potent at the cloned human neuropeptide Y Y1 receptor than at the neuropeptide Y receptor in human erythroleukemia cells, these cells may express a novel neuropeptide Y receptor with high affinity for these peptides.
Department of Central Nervous System and Cardiovascular Research, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA. eric.parker@spcorp.com
E M
EM
Parker
C K
CK
Babij
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A
Balasubramaniam
R E
RE
Burrier
M
M
Guzzi
F
F
Hamud
G
G
Mukhopadhyay
M S
MS
Rudinski
Z
Z
Tao
M
M
Tice
L
L
Xia
D E
DE
Mullins
B G
BG
Salisbury
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D006224:Cricetinae; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014162:Transfection
C097287:1229U91; C114146:BW 1991U90; D009478:Neuropeptide Y; D009842:Oligopeptides; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; C114147:T 241; C098592:neuropeptide Y (31-36), bis(31-31')(Cys(31)-Trp(32)-Nva(34)); C097212:neuropeptide Y-Y1 receptor; C109491:neuropeptide Y4 receptor