The Novel Neuropeptide Y Y1 Receptor Antagonist J-104870: A Potent Feeding Suppressant with Oral Bioavailability

Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y1 receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y1 antagonist, J-104870, shows high selectivity and potency for the Y1 receptor with an anorexigenic effect on NPY-mediated feeding. J-104870 displaced [125I]peptide YY (PYY) binding to cloned human and rat Y1 receptors with Ki values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC50 = 3.2 nM) in cells expressing human Y1 receptors. In contrast, J-104870 showed low affinities for human Y2 (Ki > 10 μM), Y4 (Ki > 10 μM), and Y5 receptors (Ki = 6 μM). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [125I]1229U91, which is known to bind to the typical Y1 receptor, with a high affinity (Ki = 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 μg) significantly suppressed NPY (5 μg)-induced feeding in satiated Sprague–Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 μg and 100 mg/kg, respectively) significantly suppressed spontaneous food intake in Zucker fatty rats. These findings suggested that J-104870 is a selective and potent nonpeptide Y1 antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y1 receptor in NPY-mediated feeding regulation. The potent and orally active Y1 antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity.