Institute of Organic Chemistry, University of Regensburg , Universitätsstrasse 31, 93053 Regensburg, Germany.
J Med Chem. 2013 Nov 14;56(21):8422-31. doi: 10.1021/jm4008505. Epub 2013 Oct 25.
Neuropeptide Y (NPY) and pancreatic polypeptide (PP) control central and peripheral processes by activating the G protein coupled receptors YxR (x = 1, 2, 4, 5). We present analogs of the C-terminal fragments 25-36 and 32-36 of NPY and PP containing (1R,2S)-cyclobutane (βCbu) or (1R,2S)-cyclopentane (βCpe) β-amino acids, which display exclusively Y4R affinity. In particular, [βCpe(34)]-NPY-(25-36) is a Y4R selective partial agonist (EC50 41 ± 6 nM, Emax 71%) that binds Y4R with a Ki of 10 ± 2 nM and a selectivity >100-fold relative to Y1R and Y2R and >50-fold relative to Y5R. Comparably, [Y(32), βCpe(34)]-NPY(PP)-(32-36) selectively binds and activates Y4R (EC50 94 ± 21 nM, Emax 73%). The NMR structure of [βCpe(34)]-NPY-(25-36) in dodecylphosphatidylcholine micelles shows a short helix at residues 27-32, while the C-terminal segment R(33)βCpe(34)R(35)Y(36) is extended. The biological properties of the βCbu- or βCpe-containing NPY and PP C-terminal fragments encourage the future application of these β-amino acids in the synthesis of selective Y4R ligands.
神经肽 Y（NPY）和胰多肽（PP）通过激活 G 蛋白偶联受体 YxR（x = 1、2、4、5）来控制中枢和外周过程。我们呈现了 NPY 和 PP 的 C 端片段 25-36 和 32-36 的类似物，其中包含（1R，2S）-环丁烷（βCbu）或（1R，2S）-环戊烷（βCpe）β-氨基酸，它们仅显示 Y4R 亲和力。特别是，[βCpe(34)]-NPY-(25-36)是一种 Y4R 选择性部分激动剂（EC50 41±6 nM，Emax 71%），与 Y4R 结合的 Ki 为 10±2 nM，与 Y1R 和 Y2R 相比具有 >100 倍的选择性，与 Y5R 相比具有 >50 倍的选择性。类似地，[Y(32)，βCpe(34)]-NPY(PP)-(32-36)选择性地结合并激活 Y4R（EC50 94±21 nM，Emax 73%）。[βCpe(34)]-NPY-(25-36)在十二烷基磷酸胆碱胶束中的 NMR 结构显示 27-32 位残基处有一个短螺旋，而 C 端片段 R(33)βCpe(34)R(35)Y(36)则延伸。这些含有βCbu 或βCpe 的 NPY 和 PP C 端片段的生物学特性鼓励未来在合成选择性 Y4R 配体时应用这些β-氨基酸。
