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A Typical Y1 Receptor Regulates Feeding Behaviors: Effects of a Potent and Selective Y1 Antagonist, J-115814
Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult to determine the relative importance of the Y1 re...
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Published in: | Molecular pharmacology 2001-03, Vol.59 (3), p.501-505 |
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Main Authors: | , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that cite this one |
Online Access: | Get full text |
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Summary: | Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect of NPY might be caused in part by the action of
Y1 receptors. However, the existence of multiple NPY receptors including a possible novel feeding receptor has made it difficult
to determine the relative importance of the Y1 receptor in feeding regulation. Herein we certified that the Y1 receptor is
a major feeding receptor of NPY by using the potent and selective Y1 antagonist (â)-2-[1-(3-chloro-5-isopropyloxycarbonylaminophenyl)ethylamino]-6-[2-(5-ethyl-4-methyl-1,3-thiazol-2-yl)ethyl]-4-morpholinopyridine
(J-115814) and Y1 receptor-deficient (Y1â/â) mice. J-115814 displaced 125 I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y 1 receptors with K i values of 1.4, 1.8, and 1.9 nM, respectively, and inhibited NPY (10 nM)-induced increases in intracellular calcium levels
via human Y1 receptors (IC 50 = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 ( K i > 10 μM), Y4 ( K i = 640 nM) and Y5 receptors ( K i = 6000 nM). Intracerebroventricular (ICV) (10â100 μg) and intravenous (IV) (0.3â30 mg/kg) administration of J-115814 significantly
and dose-dependently suppressed feeding induced by ICV NPY (5 μg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) administration
of J-115814 (3â30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by ICV NPY
(5 μg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1â/â mice and was suppressed in wild-type and Y5â/â mice. These
findings clearly suggest that J-115814 inhibits feeding behaviors through the inhibition of the typical Y1 receptor. We conclude
that the Y1 receptor plays a key role in regulating food intake. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.59.3.501 |