THE NEUROPEPTIDE-Y Y-1 ANTAGONIST, 1229U91, A POTENT AGONIST FOR THE HUMAN PANCREATIC POLYPEPTIDE-PREFERRING (NPY Y-4) RECEPTOR

Recently, a novel high-affinity peptide antagonist, 1229U91, was publi shed as a selective neuropeptide Y Y-1 antagonist. The selectivity of 1229U91 was evaluated in the human NPY Y-1 receptor containing cell li ne, SK-N-MC, and cells containing the cloned human NPY Y-2, the pancre atic polypeptide-preferring (NPY Y-4), and the NPY Y-5 receptors. 1229 U91 potently displaced [I-125]- peptide YY (PYY) binding to human NPY Y-1 receptors (IC,, = 0.245 +/- 0.004 nM, n = 4), but displayed little affinity for the human NPY Y-2 and Y-5 receptors (IC50 > 1000 nM). In terestingly, 1229U91 displaced [I-125]-PYY with even greater affinity at the human NPY Y-4 receptor (IC50 = 0.081 +/- 0.009 nM, n = 4). Usin g a cyclic AMP accumulation assay, 1229U91 blocked NPY inhibition of f orskolin-induced adenylate cyclase activity in NPY Y-1 receptor contai ning SK-N-MC cells. In the human NPY Y-4 receptor expressing cell line , 1229U91 did not block pancreatic polypeptide (PP) inhibition of fors kolin stimulated adenylate cyclase. However, in the absence of PP, 122 9U91 was able to inhibit forskolin stimulated cyclic AMP accumulation (IC50 = 7.16 +/- 2.8 nM, it = 4). We conclude that 1229U91 binds non-s electively with high affinity to both human NPY Y-1 and Y-4 receptors. Furthermore, 1229U91 displays antagonist activity at the NPY Y-1 rece ptor, while having agonist activity at the NPY Y-4 receptor. (C) 1998 Elsevier Science Inc.