title: Characterization of a novel non-steroidal glucocorticoid receptor antagonist.
abstract: Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K(i)=13.2nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.
authors.affiliation: The National Center for Drug Screening, Shanghai, China.
authors.forename: Qun-Yi
authors.initials: QY
authors.lastname: Li
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.forename: Tina M
authors.initials: TM
authors.lastname: Hallis
authors.forename: Therese A
authors.initials: TA
authors.lastname: Derosier
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Yue
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Wang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014966:Xanthenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C547208:9-(2-methylindol-3-yl)-4a-morpholino-7-nitro-1,2,3,4,4a,9a-hexahydroxanthene; D007211:Indoles; D011965:Receptors, Glucocorticoid; D014966:Xanthenes; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9