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 orexi-genic 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 selec-tive Y1 antagonist (2)-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 (Y12/2) 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 5 6.8 nM). In contrast, J-115814 showed low affinities for human Y2 (Ki. 10 mM), Y4 (Ki 5 640 nM) and Y5 receptors (Ki 5 6000 nM). Intracerebroventricular (ICV) (10–100 mg) and intravenous (IV) (0.3–30 mg/kg) administration of J-115814 significantly and dose-dependently suppressed feeding induced by ICV NPY (5 mg) in satiated Sprague-Dawley rats. Intraperitoneal (IP) admin-istration of J-115814 (3–30 mg/kg) significantly attenuated spontaneous feeding in db/db and C57BL6 mice. Feeding in-duced by ICV NPY (5 mg) was unaffected by IP-injected J-115814 (30 mg/kg) in Y12/2 mice and was suppressed in wild-type and Y52/2 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. Neuropeptide Y (NPY), a linear, 36-amino-acid peptide that belongs to a peptide family that also includes peptide YY (PYY) and pancreatic polypeptide (PP), is a potent feedin