Schober D A, Van Abbema A M, Smiley D L, Bruns R F, Gehlert D R
Lilly Neuroscience Research, Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, USA.
Peptides. 1998;19(3):537-42. doi: 10.1016/s0196-9781(97)00455-5.
Recently, a novel high-affinity peptide antagonist, 1229U91, was published as a selective neuropeptide Y Y1 antagonist. The selectivity of 1229U91 was evaluated in the human NPY Y1 receptor containing cell line, SK-N-MC, and cells containing the cloned human NPY Y2, the pancreatic polypeptide-preferring (NPY Y4), and the NPY Y5 receptors. 1229U91 potently displaced [125I]-peptide YY (PYY) binding to human NPY Y1 receptors (IC50 = 0.245+/-0.004 nM, n = 4). but displayed little affinity for the human NPY Y2 and Y5 receptors (IC50 > 1000 nM). Interestingly, 1229U91 displaced [125I]-PYY with even greater affinity at the human NPY Y4 receptor (IC50 = 0.081+/-0.009 nM, n = 4). Using a cyclic AMP accumulation assay, 1229U91 blocked NPY inhibition of forskolin-induced adenylate cyclase activity in NPY Y1 receptor containing SK-N-MC cells. In the human NPY Y4 receptor expressing cell line, 1229U91 did not block pancreatic polypeptide (PP) inhibition of forskolin stimulated adenylate cyclase. However, in the absence of PP, 1229U91 was able to inhibit forskolin stimulated cyclic AMP accumulation (IC50 = 7.16+/-2.8 nM, n = 4). We conclude that 1229U91 binds non-selectively with high affinity to both human NPY Y1 and Y4 receptors. Furthermore, 1229U91 displays antagonist activity at the NPY Y1 receptor, while having agonist activity at the NPY Y4 receptor.
最近，一种新型高亲和力肽拮抗剂1229U91作为选择性神经肽Y Y1拮抗剂被发表。在含有人NPY Y1受体的细胞系SK-N-MC以及含有克隆的人NPY Y2、胰多肽偏好型（NPY Y4）和NPY Y5受体的细胞中评估了1229U91的选择性。1229U91能有效取代[125I] - 肽YY（PYY）与人NPY Y1受体的结合（IC50 = 0.245±0.004 nM，n = 4），但对人NPY Y2和Y5受体的亲和力很低（IC50＞1000 nM）。有趣的是，1229U91与人NPY Y4受体结合取代[125I] - PYY的亲和力更高（IC50 = 0.081±0.009 nM，n = 4）。使用环磷酸腺苷积累试验，1229U91可阻断NPY对含NPY Y1受体的SK-N-MC细胞中福斯高林诱导的腺苷酸环化酶活性的抑制作用。在表达人NPY Y4受体的细胞系中，1229U91不能阻断胰多肽（PP）对福斯高林刺激的腺苷酸环化酶的抑制作用。然而，在没有PP的情况下，1229U91能够抑制福斯高林刺激的环磷酸腺苷积累（IC50 = 7.16±2.8 nM，n = 4）。我们得出结论，1229U91以高亲和力非选择性地与人NPY Y1和Y4受体结合。此外，1229U91在NPY Y1受体上表现出拮抗剂活性，而在NPY Y4受体上具有激动剂活性。
