title: Action mechanism of retinoid-synergistic dibenzodiazepines.
abstract: 4-[5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4 ]diazepin-11-yl]benzoic acid (HX600), as well as its oxa- (HX620) and thia- (HX630) analogs, enhanced the activity of retinoic acid and a receptor alpha (RAR alpha)-selective agonist Am80 in HL-60 cell differentiation assays. HX600 synergizes with Am80 by binding to, and transactivating through, the RXR subunit of the RXR-RAR heterodimer. HX600 exhibited RXR pan-agonist activity in transient transfections with a DR1-based reporter gene and synergized with RA-bound RAR alpha and RAR beta in inducing transcription from a DR5-based reporter. In addition, all three compounds at high concentrations acted as RAR pan-antagonists in stably transfected RAR "reporter cells." These efficient synergists bind only weakly with RXRs in vitro, suggesting that they are RXR-RAR heterodimer-selective activators. These HX retinoids exhibited dual functionality, since they affected signalling through both retinoid receptor families (RARs and RXRs).
authors.affiliation: Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Umemiya
authors.forename: H
authors.initials: H
authors.lastname: Kagechika
authors.forename: H
authors.initials: H
authors.lastname: Fukasawa
authors.forename: E
authors.initials: E
authors.lastname: Kawachi
authors.forename: M
authors.initials: M
authors.lastname: Ebisawa
authors.forename: Y
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: G
authors.initials: G
authors.lastname: Eisenmann
authors.forename: C
authors.initials: C
authors.lastname: Erb
authors.forename: A
authors.initials: A
authors.lastname: Pornon
authors.forename: P
authors.initials: P
authors.lastname: Chambon
authors.forename: H
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: K
authors.initials: K
authors.lastname: Shudo
mesh_terms: D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D001565:Benzoates; D003984:Dibenzazepines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C061133:tamibarotene; C104181:HX 600