The first selective agonist for the neuropeptide YY5 receptor increases food intake in rats

The first Y-5 receptor-selective analog of neuropeptide Y (NPY), [Ala(31),A ib(32)]NPY, has been developed and biologically characterized. Using compet ition binding assays on cell lines that express different Y receptors, we d etermined the affinity of this analog to be 6 nM at the human Y-5 receptor, >500 nM at the Y-1 and Y-2 receptors, and >1000 nM at the Y-4 receptor. Ac tivity studies performed in vitro using a cAMP enzyme immunoassay, and in v ivo using food intake studies in rats, showed that the peptide acted as an agonist. Further peptides obtained by the combination of the Ala(31)-Aib(32 ) motif with chimeric peptides containing segments of NPY and pancreatic po lypeptide displayed the same selectivity and even higher affinity (up to 0. 2 nM) for the Y-5 receptor. In vivo administration of the new Y-5 receptor- selective agonists significantly stimulated feeding in rats. The NMR soluti on structures of NPY and [Ala(31),Aib(32)]NPY showed a different conformati on in the C-terminal region, where the or-helix of NPY was substituted by a more flexible, 3(10)-helical turn structure.