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Molecular characterization of the ligand–receptor interaction of the neuropeptide Y family
Author(s) -
Cabrele Chiara,
BeckSickinger Annette G.
Publication year - 2000
Publication title -
journal of peptide science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 66
eISSN - 1099-1387
pISSN - 1075-2617
DOI - 10.1002/(sici)1099-1387(200003)6:3<97::aid-psc236>3.0.co;2-e
Subject(s) - neuropeptide y receptor , receptor , peptide yy , g protein coupled receptor , chemistry , 5 ht5a receptor , peptide , enzyme linked receptor , ligand (biochemistry) , biochemistry , biology , neuropeptide
Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong 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 coupled receptors. Structure–affinity and structure–activity relationship studies of peptide analogs, combined with studies based on site‐directed mutagenesis and anti‐receptor antibodies, have given insight into the individual characterization of each receptor subtype relative to its interaction with the ligand, as well as to its biological function. A number of selective antagonists at the Y 1 ‐receptor are available whose structures resemble that of the C ‐terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in vivo investigations of the NPY‐induced increase in food intake. Y 2 ‐receptor selective agonists are the analog cyclo‐(28/32)‐Ac‐[Lys 28 ‐Glu 32 ]‐(25–36)‐pNPY and the TASP molecule containing two units of the NPY segment 21–36. Now the first antagonist with nanomolar 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 ‐receptor. However, by the design of PP/NPY chimera, some analogs have been found that bind not only to the Y 4 ‐, but also to the Y 5 ‐receptor with subnanomolar affinities, and are as potent as NPY at the Y 1 ‐receptor. For the characterization of the Y 5 ‐receptor in vitro and in vivo , a new class of highly selective agonists is now available. This consists of analogs of NPY and of PP/NPY chimera which all contain the motif Ala 31 ‐Aib 32 . This motif 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. The results of feeding experiments in rats treated with the first highly specific Y 5 ‐receptor agonists support the hypothesis that this receptor plays a role in the NPY‐induced stimulation of food intake. In conclusion, the selective compounds for the different Y‐receptor subtypes known so far are promising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors. Copyright © 2000 European Peptide Society and John Wiley & Sons, Ltd.