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Vol. 59, Issue 3, 501-505, March 2001

A Typical Y1 Receptor Regulates Feeding Behaviors: Effects of a Potent and Selective Y1 Antagonist, J-115814

Akio Kanatani, Mikiko Hata, Satoshi Mashiko, Akane Ishihara, Osamu Okamoto, Yuji Haga, Tomoyuki Ohe, Tetsuya Kanno, Naomi Murai, Yasuyuki Ishii, Takahiro Fukuroda, Takehiro Fukami, and Masaki Ihara

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan

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 (-)-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 (Y1-/-) mice. J-115814 displaced 125I-peptide YY binding to cell membranes expressing cloned human, rat, and murine Y1 receptors with Ki 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 (IC50 = 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (Ki > 10 µM), Y4 (Ki = 640 nM) and Y5 receptors (Ki = 6000 nM). Intracerebroventricular (ICV) (10-100 µg) and intravenous (IV) (0.3-30 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 (3-30 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 Y1-/- mice and was suppressed in wild-type and Y5-/- 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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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