Stereochemical probes for the estrogen receptor: synthesis and receptor binding of (17 alpha,20E/Z)-21-phenyl-19-norpregna-1,3,5(10), 20-tetraene-3,17 beta-diols.
Previous studies from our laboratory using 17 alpha-E- and 17 alpha-Z-halovinyl and phenylthiovinyl estradiols demonstrated a marked preference for the Z stereochemistry and a significant steric tolerance for the Z-vinyl substituent. To further explore the extent of that stereochemical preference and steric tolerance we have prepared stereoselectively the 17 alpha-E- and 17 alpha-Z-phenylvinyl estradiols (E- and Z-styrylestradiols). The results, in addition to demonstrating a facile preparation of the target compounds, supported the previously observed stereochemical and steric effects. The relative binding affinities for the Z isomer were 3-4 fold greater than the E isomer at both 4 degrees C and 25 degrees C, and only one-half to one-fourth those of estradiol under similar conditions. The developing model for ligand-accessible space within the estrogen receptor suggests that Z-phenylvinyl estradiols may provide interesting and useful probes for mapping the receptor.
Hanson
R N
RN
Department of Pharmaceutical Sciences, Bouve College of Pharmacy and Health Sciences, Northeastern University, Boston 02115, USA.
Herman
L W
LW
Fiaschi
R
R
Napolitano
E
E
D001665:Binding Sites; D001667:Binding, Competitive; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011960:Receptors, Estrogen; D004958:Estradiol