Selective glucocorticoid receptor nonsteroidal ligands completely antagonize the dexamethasone mediated induction of enzymes involved in gluconeogenesis and glutamine metabolism.

Glucocorticoids (GCs) are vital multi-faceted hormones with recognized effects on carbohydrate, protein and lipid metabolism. Previous studies with the steroid antagonist, RU486 have underscored the essential role of GCs in the regulation of these metabolic pathways. This article describes the discovery and characterization of novel GRalpha selective nonsteroidal antagonists (NSGCAs). NSGCAs 2 and 3 are spirocyclic dihydropyridine derivatives that selectively bind the GRalpha with IC(50s) of 2 and 1.5 nM, respectively. Importantly, these compounds are full antagonists of the induction by dexamethasone (Dex) of marker genes for glucose and glutamine metabolism; the tyrosine amino transferase (TAT) and glutamine synthetase (GS) enzymes, respectively. In contrast, GC-dependent transcriptional repression of the collagenase 1 (MMP-1) enzyme, an established GRalpha responsive proinflammatory gene; is poorly antagonized by these compounds. These NSGCAs might have useful applications as tools in metabolic research and drug discovery.