MODIFIED, CYCLIC DODECAPEPTIDE ANALOG OF NEUROPEPTIDE-Y IS THE SMALLEST FULL AGONIST AT THE HUMAN Y-2 RECEPTOR

In order to stabilize the C-terminal dodecapeptide of neuropeptide Y ( NPY) we replaced Leu(28) and Thr(32) by Lys and Glu, respectively, and subsequently linked these residues by lactamization. This peptide ana log of NPY shows a more than 100-fold increase in affinity compared to the C-terminal linear dodecapeptide in receptor binding studies perfo rmed at human neuroblastoma cells SMS-KAN, which exclusively express t he Y-2 receptor subtype, Signal transduction was investigated by measu ring Ca2+ current inhibition in human SH-SY5Y cells and cyclic [Lys(28 )-Glu(32)] NPY Ac-25-36 and NPY were shown to be equipotent in this as say, Thus, this molecule is the smallest Y-2 receptor selective full a gonist of NPY. Using 2D-NMR experiments and molecular modelling techni ques, the structures of the linear and cyclic peptides have been inves tigated and significant differences have been found, which may explain the improvement in biological activity, Thus, a model of the bioactiv e conformation of NPY at the human Y-2 receptor is suggested.