title: Pharmacological characterization and feeding-suppressive property of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel, selective, and orally active antagonist for neuropeptide Y Y5 receptor.
abstract: We evaluated the pharmacological profiles of FMS586 [3-(5,6,7,8-tetrahydro-9-isopropyl-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride], a novel tetrahydrocarbazole derivative as a neuropeptide Y (NPY) Y5 receptor antagonist. This compound showed a highly selective in vitro affinity for Y5 (IC(50) = 4.3 +/- 0.4 nM) relative to other NPY receptor subtypes like Y1 or Y2. Its binding to Y5 was found to be fully antagonistic from cyclic AMP accumulation assays in human embryonic kidney 293 cells. Pharmacokinetic analysis revealed sufficient oral availability and brain permeability of this compound accompanied with clear dose relation. We attempted to assess the selectivity of FMS586 and, thereby, to infer the physiological role of Y5 in the following feeding experiments in normal rats. An intracerebroventricular injection of NPY and Y5-selective agonist peptide induced acute and robust feeding responses in satiated rats, and prior administration of FMS586 at the doses from 25 to 100 mg/kg clearly inhibited these responses by approximately 55 and 90%, respectively. This compound also showed dose-dependent but transient suppression in natural feeding models of both overnight fasting-induced hyperphagia and spontaneous daily intake. FMS586 did not modulate food intake induced by the topical injection of norepinephrine, galanin, or gamma-aminobutyric acid receptor agonist muscimol to the paraventricular nucleus. In addition, we confirmed the Y5-specific activity profile of FMS586 by immunohistochemical analysis. Taken together, we propose not only that our compound potentially expresses specific blockade of central Y5 signals but also that Y5 receptor would certainly contribute to physiological regulation of food intake in normal rats, as suggested from its origin.
authors.affiliation: Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760, Moro-oka-cho, Kohoku-ku, Yokohama 222-8567, Japan. nobukazu_kakui@meiji.co.jp
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Kakui
authors.forename: Jiro
authors.initials: J
authors.lastname: Tanaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tabata
authors.forename: Kenji
authors.initials: K
authors.lastname: Asai
authors.forename: Naomi
authors.initials: N
authors.lastname: Masuda
authors.forename: Takako
authors.initials: T
authors.lastname: Miyara
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nakatani
authors.forename: Fukuichi
authors.initials: F
authors.lastname: Ohsawa
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Masaharu
authors.initials: M
authors.lastname: Sugai
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kozo
authors.initials: K
authors.lastname: Aoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitaguchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001067:Appetite Depressants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D006963:Hyperphagia / Q000188:drug therapy* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008782:Methylurea Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*
chemical_list: C510787:3-(5,6,7,8-tetrahydro-9-isopropylcarbazol-3-yl)-1-methyl-1-(2-pyridin-4-ylethyl)urea; D001067:Appetite Depressants; D002227:Carbazoles; D008782:Methylurea Compounds; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor; D000242:Cyclic AMP