A novel neuropeptide Y analog, N-acetyl [Leu28,Leu31]neuropeptide Y-(24-36), with functional specificity for the presynaptic (Y2) receptor.

Abstract We have carried out functional and in vitro studies on a novel analog of neuropeptide Y which shows selectivity for the prejunctional or neuropeptide Y Y 2 receptor. In anaesthetised rats N -acetyl [Leu 28 , Leu 31 ]neuropeptide Y-(24–36) attenuates cardiac vagal action (a prejunctional or neuropeptide Y Y 2 action) and has no significant pressor effects (postjunctional or neuropeptide Y Y 1 action). In the human neuroblastoma cell line (SMS-KAN) which expresses an endogenous Y 2 -like neuropeptide Y receptor, N -acetyl [Leu 28 , Leu 31 ]neuropeptide Y-(24–36) competes with peptide YY for binding sites with an IC 50 of 0.5 ± 0.1 nM. In contrast in a fibroblast Chinese hamster ovary cell line which expresses the cloned human neuropeptide Y Y 1 receptor and is used to study changes in cytosolic calcium evoked by (a neuropeptide Y Y 1 effect), N -acetyl [Leu 28 , Leu 31 ]neuropeptide Y-(24–36) showed no activity even at high concentrations. The steric structure for this novel compound has been determined using proton nuclear magnetic resonance (NMR) spectroscopy and it is consistent with the C-terminal end of published structures of neuropeptide Y. We suggest acetylation and amino acid substitutions stabilise the molecule and allow it to bind only to the neuropeptide Y Y 2 receptor.