title: Synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor.
abstract: Adverse effects of glucocorticoids could be limited by developing new compounds that selectively modulate anti-inflammatory activity of the glucocorticoid receptor (GR). We have synthesized a novel series of steroidal GR ligands, including potent agonists, partial agonists and antagonists with a wide range of effects on inhibiting secretion of interleukin-6. Some of these new ligands were designed to directly impact conformational stability of helix-12, in the GR ligand-binding domain (LBD). These compounds modulated GR activity and glucocorticoid-induced gene expression in a manner that was inversely correlated to the degree of inflammatory response. In contrast, compounds designed to directly modulate LBD epitopes outside helix-12, led to dissociated levels of GR-mediated gene expression and inflammatory response. Therefore, these new series of compounds and their derivatives will be useful to dissect the ligand-dependent features of GR signaling specificity.
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Jin
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Sathish
authors.initials: S
authors.lastname: Srinivasan
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Jerome C
authors.initials: JC
authors.lastname: Nwachukwu
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Bruno
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Kendall W
authors.initials: KW
authors.lastname: Nettles
authors.affiliation: Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: kameneck@scripps.edu.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000093242:Interleukin-6 Inhibitors
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D013256:Steroids; D000093242:Interleukin-6 Inhibitors
keywords: Agonist; Antagonist; Glucocorticoid receptor; Partial agonist