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Vol. 60, Issue 3, 534-540, September 2001
Department of Central Nervous System and Cardiovascular Research,
Schering-Plough Research Institute, Kenilworth, New Jersey (D.M.,
J.H., M.G., E.P.); and Clayton Foundation Laboratories for Peptide
Biology, The Salk Institute, La Jolla, California (D.K., J.R.)
Neuropeptide Y (NPY) binds to a family of G-protein coupled receptors
termed Y1, Y2, Y3, Y4,
Y5, and y6. The use of various receptor
subtype-selective agonists and antagonists has facilitated identification of the receptor subtypes responsible for mediating many
of the biological effects of NPY. For example, the potent orexigenic
activity of NPY is believed to be mediated by both the Y1
and Y5 receptor subtypes. Several selective Y5
receptor agonists that stimulate food intake in rodents are available, but no selective Y1 receptor agonist has been reported. We
have identified several NPY analogs that bind the NPY Y1
receptor with high affinity and exhibit full agonist activity, measured
as inhibition of forskolin-stimulated cAMP production in cells
expressing the cloned NPY Y1 receptor.
[D-Arg25]-NPY,
[D-His26]-NPY,
Des-AA10-17[Cys7,21,Pro34]-NPY,
Des-AA11-18[Cys7,21,D-Lys9(Ac)]-NPY,
Des-AA11-18[Cys7,21,D-Lys9(Ac),Pro34]-NPY,
Des-AA11-18[Cys7,21,D-Lys9(Ac),D-His26]-NPY
and
Des-AA11-18[Cys7,21,D-Lys9(Ac),D-His26, Pro34]-NPY
bind the NPY Y1 receptor with Ki
values of 0.9 ± 0.2, 2.0 ± 0.3, 0.2 ± 0.05, 0.7 ± 0.1, 0.2 ± 0.01, 2.2 ± 0.3, and 1.2 ± 0.3 nM,
respectively, and inhibit forskolin-stimulated cAMP production with
EC50 values of 0.2 ± 0.02, 0.5 ± 0.04, 0.3 ± 0.03, 0.5 ± 0.05, 0.4 ± 0.16, 5.3 ± 0.32, and
5.1 ± 0.97 nM, respectively. These peptides are highly selective
for the NPY Y1 receptor relative to the NPY Y2,
Y4, and Y5 receptors.
[D-Arg25]-NPY,
[D-His26]-NPY and
Des-AA11-18[Cys7,21, D-Lys9(Ac),D-His26,Pro34]-NPY
stimulate food intake dose-responsively in Long-Evans rats for at
least 4 h after intracerebroventricular administration. Although
the involvement of Y1 receptors in several physiological activities, such as vasoconstriction and anxiolysis, remains to be investigated, adequate tools are now available.
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