C. Cabrele et Ag. Beck-sickinger, Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family, J PEPT SCI, 6(3), 2000, pp. 97
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.