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J Med Chem ; 61(11): 4720-4738, 2018 06 14.
Article in English | MEDLINE | ID: mdl-29741891

ABSTRACT

Estrogen receptor-beta (ERß) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERß agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the ß over α isoform and with EC50s of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.


Subject(s)
Estrogen Receptor beta/agonists , Estrogens/chemistry , Estrogens/pharmacology , Memory Consolidation/drug effects , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , Estrogen Receptor beta/chemistry , Estrogen Receptor beta/metabolism , Estrogens/metabolism , Humans , MCF-7 Cells , Molecular Docking Simulation , Protein Conformation , Structure-Activity Relationship
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