Dihydropyridine neuropeptide Y Y1 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).