The novel neuropeptide YY1 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, Y-1 receptors may play a key role in feeding regulation. In the present study, me demonstrated that a novel Y, antagonist, J-104870, shows high selectivity and potency for the Y-1 receptor with an anorexigenic effect on NPY-mediated feeding. J-104870 displaced [I-125]peptide YY (PYY) binding to cloned human and rat Y, receptors with Ri 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 Y-1 receptors. In contrast, J-104870 showed low affinities for human Y-2 (K-i > 10 mu M), Y-4 (K-i > 10 mu M), and Y-5 receptors (K-i = 6 mu M). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [I-125]1229U91, which is known to bind to the typical Y-1 receptor, with a high affinity (K-i = 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 mu g) significantly suppressed NPY (5 mu g)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 mu g 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 Y, antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y-1 receptor in NPY-mediated feeding regulation. The potent and orally active Y-1 antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity. (C) 1999 Academic Press.