A–C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions

Estrogen
receptor-beta (ERβ) is a drug target for memory consolidation
in postmenopausal women. Herein is reported a series of potent and
selective ERβ 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 β 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.