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.