title: Synthesis and evaluation of isomeric (17alpha,20E)-11beta-methoxy-21-(trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols as ERalpha-hormone binding domain ligands: effect of the methoxy group on receptor binding and uterotrophic growth.
abstract: In this study we have introduced the 11beta-methoxy group, a substituent known to increase in vivo potency in other steroidal estrogens, into the (17alpha,20E)-21-(trifluoromethylphenyl)-19-norpregna-1,3,5(10),20-tetraene-3,17beta-diols: (trifluoromethylphenyl)vinyl estradiols. Receptor binding, using the ERalpha-HBD, indicated that the 11beta-methoxy group had little effect on the relative binding affinity of the target compounds compared to the corresponding 11beta-unsubstituted analogs, however, the 11beta-methoxy derivatives were significantly more potent in stimulating uterotrophic growth in immature female rats. Molecular modeling studies suggest that while the 11beta-methoxy group does not contribute significantly to the overall binding energy of the ligand-ERalpha-HBD complex, it stabilizes residues associated with the coregulator protein binding site. Such effects would influence the dynamics of subsequent events, such as transcription and biological responses.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA. r.hanson@neu.edu
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hanson
authors.forename: Pakamas
authors.initials: P
authors.lastname: Tongcharoensirikul
authors.forename: Robert
authors.initials: R
authors.lastname: Dilis
authors.forename: Alun
authors.initials: A
authors.lastname: Hughes
authors.forename: Eugene R
authors.initials: ER
authors.lastname: Desombre
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism*; D004967:Estrogens / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D008024:Ligands; D008958:Models, Molecular; D009651:Norpregnatrienes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects*
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D008024:Ligands; D009651:Norpregnatrienes