title: Retinoid receptor subtype-selective modulators through synthetic modifications of RARgamma agonists.
abstract: A series of retinoids designed to interfere with the repositioning of H12 have been synthesized to identify novel RARgamma antagonists based on the structure of known RARgamma agonists. The transcriptional activities of the novel ligands were revealed by cell-based reporting assays, using engineered cells containg RAR subtype-selective fusions of the RAR ligand-binding domains with the yeast GAL4 activator DNA-binding domain and the cognate luciferase reporter gene. Whereas none of the ligands exhibited features of a selective RARgamma antagonist, some of them are endowed with interesting activities. In particular 24a acts as a pan-RAR agonist that induces at high concentration a higher transactivation potential on RARalpha than TTNPB and synergizes at low concentration with TTNPB-bound RARalpha but not RARbeta or RARgamma. Similarly, 24c synergizes with TTNPB-bound RARgamma and exhibits RARalpha,beta antagonist activity. Compounds 24b and 25b are strong RARalpha,beta-selective antagonists without agonist or antagonist activities for RARgamma. Compounds 24b and 24c display weak RXR antagonist activity. In addition several pan-antagonists and partial agonist/antagonists have been defined.
authors.affiliation: Departamento de Química Orgánica, Universidade de Vigo, Vigo, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Rosana
authors.initials: R
authors.lastname: Alvarez
authors.forename: Harshal
authors.initials: H
authors.lastname: Khanwalkar
authors.forename: Pierre
authors.initials: P
authors.lastname: Germain
authors.forename: Géraldine
authors.initials: G
authors.lastname: Lemaire
authors.forename: Fátima
authors.initials: F
authors.lastname: Rodríguez-Barrios
authors.forename: Hinrich
authors.initials: H
authors.lastname: Gronemeyer
authors.forename: Angel R
authors.initials: AR
authors.lastname: de Lera
mesh_terms: D002352:Carrier Proteins; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011993:Recombinant Fusion Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D002352:Carrier Proteins; D008024:Ligands; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D012176:Retinoids