Zusammenfassung
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), which display exclusively Y4R affinity. In particular, [βCpe34]-NPY-(25-36) is a Y4R ...
Zusammenfassung
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), which display exclusively Y4R affinity. In particular, [βCpe34]-NPY-(25-36) is a Y4R selective partial agonist (EC50 41±6 nM, Emax 71%), which 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, [Y32, βCpe34]-NPY(PP)-(32-36) selectively binds and activates Y4R (EC50 94±21 nM, Emax 73%). The NMR structure of [βCpe34]-NPY-(25-36) in dodecylphosphatidylcholine micelles shows a short helix at residues 27-32, while the C-terminal segment R33βCpe34R35Y36 is extended. The biological properties of the βCbu- or βCpe-containing NPY and PP C-terminal fragments encourage the future application of these cyclic β-amino acids in the synthesis of selective Y4R ligands.
Altmetric