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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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2002-02, Vol.12 (3), p.379-382
Main Authors: 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: Article
Language:English
Subjects:
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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Summary: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