title: Dihydropyridine neuropeptide Y Y(1) receptor antagonists.
abstract: Dihydropyridine 5a was found to be an inhibitor of neuropeptide Y(1) binding in a high throughput (125)I-PYY screening assay. Structure-activity studies around certain portions of the dihydropyridine chemotype identified BMS-193885 (6e) as a potent and selective Y(1) receptor antagonist. In a forskolin-stimulated c-AMP production assay using CHO cells expressing the human Y(1) receptor, 6e demonstrated full functional antagonism (K(b)=4.5 nM). Compound 6e inhibited NPY-induced feeding in satiated rats when dosed at 3.0 and 10.0 mg/kg (ip), and also decreased spontaneous overnight food consumption in rats at doses of 10 and 20 mg/kg (ip).
authors.affiliation: Pharmaceutical Research Institute, Bristol-Myers Squibb Co., 5 Research Parkway, 06492-7660, Wallingford, CT 06492-7660, USA. graham.poindexter@bms.com
authors.forename: Graham S
authors.initials: GS
authors.lastname: Poindexter
authors.forename: Marc A
authors.initials: MA
authors.lastname: Bruce
authors.forename: Karen L
authors.initials: KL
authors.lastname: LeBoulluec
authors.forename: Ivo
authors.initials: I
authors.lastname: Monkovic
authors.forename: Scott W
authors.initials: SW
authors.lastname: Martin
authors.forename: Eric M
authors.initials: EM
authors.lastname: Parker
authors.forename: Larry G
authors.initials: LG
authors.lastname: Iben
authors.forename: Rachel T
authors.initials: RT
authors.lastname: McGovern
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Ortiz
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Stanley
authors.forename: Gail K
authors.initials: GK
authors.lastname: Mattson
authors.forename: Michael
authors.initials: M
authors.lastname: Kozlowski
authors.forename: Meredith
authors.initials: M
authors.lastname: Arcuri
authors.forename: Ildiko
authors.initials: I
authors.lastname: Antal-Zimanyi
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D019440:Anti-Obesity Agents; C456407:BMS 193885; D004095:Dihydropyridines; D010671:Phenylurea Compounds; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor