title: A potent nonpeptide neuropeptide Y Y1 receptor antagonist, a benzodiazepine derivative.
abstract: We describe here a nonpeptide neuropeptide Y Y1 receptor antagonist, 2,4-dioxo-1,5-bis(2-oxo-2-orthotolyl-ethyl)-3-[3-[3-([3-[3-(3-p iperidin-1-ylmethyl-phenoxy)-propylcarbamoyl]-propyl]-car bamoyloxymethyl)-phenyl]-ureido]-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaz epine (Compound 1), which was previously synthesized as a linked type of dual cholecystokinin (CCK)-B and histamine H2 receptor antagonist. Compound 1 competitively inhibited [125I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells with Ki of 6.4 +/- 1.0 nM, while it had no effect on [125I]PYY binding to Y2 or Y5 receptors even at 1 microM. Functionally, Compound 1 inhibited the Y1 receptor-mediated increase in cytosolic free Ca2+ concentration and Y1 receptor-mediated attenuation of cAMP accumulation in a dose-dependent manner with IC50 values of 95 +/- 5 and 320 +/- 10 nM in SK-N-MC cells, respectively. Neither its CCK-B receptor antagonistic moiety of Compound 1 (Compound 2) nor its histamine H2 receptor antagonistic moiety of Compound 1 (Compound 3) had any effect on [125I]PYY binding, suggesting that the entire structure of Compound 1 is essential for Y1 receptor blocking activity. It showed no significant activity (IC50 > 1 microM) in 30 receptor binding assays and 5 enzyme assays, with the exception of CCK-B and histamine H2 receptors. We conclude that Compound 1 is a useful molecule not only for studying the physiological role of neuropeptide Y but also for exploring more specific Y1 receptor antagonists.
authors.affiliation: Shionogi Research Laboratories, Shionogi and Co., Ltd., Osaka, Japan. shigeri@onri.go.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Shigeri
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Ishihara
authors.forename: M
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D008297:Male; D011485:Protein Binding; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014407:Tumor Cells, Cultured
chemical_list: D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D001569:Benzodiazepines