Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

Neuropeptide Y (NP7), peptide YY (PYY) and pancreatic polypeptide (PP) belo ng to the NPY hormone family and activate a class of receptors called the Y -receptors, and also belong to the large superfamily of the G-protein coupl ed receptors. Structure-affinity and structure-activity relationship studie s of peptide analogs, combined with studies based on site-directed mutagene sis and anti-receptor antibodies, have given insight into the individual ch aracterization of each receptor subtype relative to its interaction with th e ligand, as well as to its biological function. A number of selective anta gonists at the Y-1-receptor are available whose structures resemble that of the C-terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 an d GW1229, have recently been used for in vivo investigations of the NPY-ind uced increase in food intake. Y-2-receptor selective agonists are the analo g cyclo-(28/32)-Ac[Lys(28)-Glu(32)]-(25-36)-pNPY and the TASP molecule cont aining two units of the NPY segment 21-36. Now the first antagonist with na nomolar affinity for the Y-2-receptor is also known, BIIE0246. So far, the native peptide PP has been shown to be the most potent ligand at the Y-4-re ceptor. However. by the design of PP/NPY chimera, some analogs have been fo und that bind not only to the Y-4-, but also to the Y-5-receptor with subna nomolar affinities, and are as potent as NPY at the Y-1-receptor. For the c haracterization of the Y-5-receptor in vitro,and in vivo, a new class of hi ghly selective agonists is now available. This consists of analogs of NPY a nd of PP/NPY chimera which all contain the motif Ala(31)-Aib(32). This moti f has been shown ;to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be the key motif for high Y-5-receptor selectivity. Th e results of feeding experiments in rats treated with the first highly spec ific Y-5-receptor agonists support the hypothesis that this receptor plays a role in the NPY-induced stimulation of food intake. In conclusion. the se lective compounds for the different Y-receptor subtypes known so far are pr omising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors, Copyright (C) 2000 E uropean Peptide Society and John Wiley & Sons, Ltd.