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[摘要]：The discovery, pharmacology, and biophysical characterization of an estrogen receptor alpha (ER alpha) selective benzothiophene (BTP alpha) is described. BTP alpha (4) is a high-affinity ligand with 140-fold greater selectivity for ER alpha (K-i = 0.25 nM) over estrogen receptor beta (ER beta) (K-i = 35 nM). In rodent models of estrogen action, BTP alpha blocks the effects of estrogen in the uterus but mimics the effects of estrogen on bone. The basis of ERa selectivity for BTP alpha was evaluated by using protein crystallography and hydrogen/deuterium exchange (HDX) mass spectrometry. HDX data support that the n-butyl chain of BTP alpha stabilizes helix 7 in ER alpha relative to that of ER beta, which we propose leads to an enhancement of affinity to the alpha-receptor subtype. |
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