TY - JOUR
T1 - Differential response of estrogen receptor subtypes to 1,3-diarylindene and 2,3-diarylindene ligands
AU - Clegg, Nicola J.
AU - Paruthiyil, Sreenivasan
AU - Leitman, Dale C.
AU - Scanlan, Thomas S.
PY - 2005/9/22
Y1 - 2005/9/22
N2 - Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERα and ERβ in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERα and ERβ subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERα, while antagonizing estradiol action at ERβ.
AB - Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERα and ERβ in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERα and ERβ subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERα, while antagonizing estradiol action at ERβ.
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U2 - 10.1021/jm050226i
DO - 10.1021/jm050226i
M3 - Article
C2 - 16162002
AN - SCOPUS:24944569173
SN - 0022-2623
VL - 48
SP - 5989
EP - 6003
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 19
ER -