title: The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability.
abstract: 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, we demonstrated that a novel Y(1) antagonist, J-104870, shows high selectivity and potency for the Y(1) receptor with an anorexigenic effect on NPY-mediated feeding. J-104870 displaced [(125)I]peptide YY (PYY) binding to cloned human and rat Y(1) receptors with K(i) values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC(50) = 3.2 nM) in cells expressing human Y(1) receptors. In contrast, J-104870 showed low affinities for human Y(2) (K(i) > 10 microM), Y(4) (K(i) > 10 microM), and Y(5) receptors (K(i) = 6 microM). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [(125)I]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 microg) significantly suppressed NPY (5 microg)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 microg 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(1) 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.
authors.affiliation: Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba, 300-2611, Japan. kantniak@banyu.co.jp
authors.forename: A
authors.initials: A
authors.lastname: Kanatani
authors.forename: T
authors.initials: T
authors.lastname: Kanno
authors.forename: A
authors.initials: A
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Hata
authors.forename: A
authors.initials: A
authors.lastname: Sakuraba
authors.forename: T
authors.initials: T
authors.lastname: Tanaka
authors.forename: Y
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: T
authors.initials: T
authors.lastname: Mase
authors.forename: T
authors.initials: T
authors.lastname: Fukuroda
authors.forename: T
authors.initials: T
authors.lastname: Fukami
authors.forename: M
authors.initials: M
authors.lastname: Ihara
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002219:Carbamates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D005247:Feeding Behavior / Q000187:drug effects*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007276:Injections, Intraventricular; D008297:Male; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D002219:Carbamates; C402393:J 104870; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D013844:Thiazoles; C097212:neuropeptide Y-Y1 receptor