Kanatani A, Ishihara A, Iwaasa H, Nakamura K, Okamoto O, Hidaka M, Ito J, Fukuroda T, MacNeil D J, Van der Ploeg L H, Ishii Y, Okabe T, Fukami T, Ihara M
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Japan.
Biochem Biophys Res Commun. 2000 May 27;272(1):169-73. doi: 10.1006/bbrc.2000.2696.
Neuropeptide Y (NPY) elicits food intake through the action of hypothalamic G-protein-coupled receptors. Previous publications indicate that the Y5 receptor may represent one of these postulated hypothalamic "feeding" receptors. Using a potent and orally available Y5 antagonist L-152,804, we evaluated the involvement of the Y5 receptor in feeding regulation. L-152,804 displaced [125I]peptide YY (PYY) binding to human and rat Y5 receptors with Ki values of 26 and 31 nM, respectively, and inhibited NPY (100 nM)-induced increase in intracellular calcium levels via human Y5 receptors (IC50 = 210 nM). L-152,804 did not show significant affinity for human Y1, Y2, and Y4 receptors at a dose of 10 microM. Intracerebroventricular (i.c.v.) (30 microg) or oral (10 mg/kg) administration of L-152,804 significantly inhibited food intake evoked by i.c.v.-injected bovine pancreatic peptide (bPP, 5 microg; a moderately selective Y4, Y5 agonist) in satiated SD rats. However L-152,804 did not significantly inhibit i.c.v. NPY (5 microg; a Y1, Y2, Y5 agonist)-induced food intake. These findings suggest that L-152,804 is a selective and potent non-peptide Y5 antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effects of L-152,804 on bPP-induced feeding revealed participation of the Y5 receptor in feeding regulation, while i.c.v. administration of NPY does not appear to significantly contribute to Y5 stimulated food intake. We conclude that the potent and orally active Y5 antagonist, L-152,804, represents a useful tool to address the physiological role of the Y5 receptor.
神经肽Y（NPY）通过下丘脑G蛋白偶联受体的作用引发食物摄入。先前的出版物表明，Y5受体可能是这些假定的下丘脑“进食”受体之一。使用一种强效且口服有效的Y5拮抗剂L-152,804，我们评估了Y5受体在进食调节中的作用。L-152,804分别以26和31 nM的Ki值取代[125I]肽YY（PYY）与人及大鼠Y5受体的结合，并通过人Y5受体抑制NPY（100 nM）诱导的细胞内钙水平升高（IC50 = 210 nM）。在10 μM的剂量下，L-152,804对人Y1、Y2和Y4受体没有显示出明显的亲和力。向饱腹的SD大鼠脑室内（i.c.v.）注射（30 μg）或口服（10 mg/kg）L-152,804可显著抑制由脑室内注射牛胰肽（bPP，5 μg；一种中度选择性的Y4、Y5激动剂）诱发的食物摄入。然而，L-152,804并没有显著抑制脑室内注射NPY（5 μg；一种Y1、Y2、Y5激动剂）诱导的食物摄入。这些发现表明，L-152,804是一种具有口服生物利用度和脑渗透性的选择性强效非肽Y5拮抗剂。此外，L-152,804对bPP诱导的进食的厌食作用揭示了Y5受体参与进食调节，而脑室内注射NPY似乎对Y5刺激的食物摄入没有显著贡献。我们得出结论，强效且口服活性的Y5拮抗剂L-152,804是研究Y5受体生理作用的有用工具。
