Dihydropyridine neuropeptide Y Y(1) receptor antagonists

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 forsko...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2002-02, Vol.12 (3), p.379-382
Hauptverfasser:	Poindexter, Graham S, Bruce, Marc A, LeBoulluec, Karen L, Monkovic, Ivo, Martin, Scott W, Parker, Eric M, Iben, Larry G, McGovern, Rachel T, Ortiz, Astrid A, Stanley, Jennifer A, Mattson, Gail K, Kozlowski, Michael, Arcuri, Meredith, Antal-Zimanyi, Ildiko
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anti-Obesity Agents - chemical synthesis Anti-Obesity Agents - pharmacology Cell Line Cell Membrane - drug effects Cell Membrane - metabolism CHO Cells Cricetinae Dihydropyridines - chemical synthesis Dihydropyridines - pharmacology Eating - drug effects Humans Kinetics Phenylurea Compounds - chemical synthesis Phenylurea Compounds - pharmacology Radioligand Assay Rats Receptors, Neuropeptide Y - antagonists & inhibitors Structure-Activity Relationship
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Zusammenfassung:	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).
ISSN:	0960-894X