A typical y1 receptor regulates feeding behaviors: Effects of a potent andselective Y1 antagonist, J-115814

Neuropeptide Y (NPY) is a potent feeding stimulant. The orexigenic effect o f NPY might be caused in part by the action of Y1 receptors. However, the e xistence of multiple NPY receptors including a possible novel feeding recep tor has made it difficult to determine the relative importance of the Y1 re ceptor in feeding regulation. Herein we certified that the Y1 receptor is a major feeding receptor of NPY by using the potent and selective Y1 antagon ist (-)-2-[1-(3- chloro-5-isopropyloxycarbon-ylaminophenyl)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 I-125- peptide YY binding to cell membranes expressing cloned human, rat, and murine Y1 re ceptors with K-i values of 1.4, 1.8, and 1.9 nM, respectively, and inhibite d NPY (10 nM)-induced increases in intracellular calcium levels via human Y 1 receptors (IC50 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (K-i > 10 muM), Y4 (K-i = 640 nM) and Y5 receptors (K-i = 6000 nM) . Intracerebroventricular (ICV) (10-100 mug) and intravenous (IV) (0.3- 30 mg/kg) administration of J-115814 significantly and dose-dependently suppre ssed feeding induced by ICV NPY (5 mug) in satiated Sprague-Dawley rats. In traperitoneal (IP) administration of J-115814 (3-30 mg/kg) significantly at tenuated spontaneous feeding in db/db and C57BL6 mice. Feeding induced by I CV NPY (5 mug) was unaffected by IP-injected J-115814 (30 mg/kg) in Y1-/- m ice 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.