Estrogens (17b-estradiol, E2) have been garnered considerable attention over past decades in influencing cognitive process in relation to phases of the menstrual cycle, aging and menopausal symptoms. However, hormone replacement therapy can have deleterious effects leading to breast and endometrial cancer, predominantly mediated by estrogen receptor-alpha (ERa) the major isoform present in the mammary gland and uterus. Conversely, accumulating evidence supports for a dominant role of estrogen receptor-beta (ERb) for improved cognitive effects such enhanced hippocampal signaling and memory consolidation via ERK/MAPK signaling cascade. Thus, an exciting new direction in drug discovery is designing of ERb selective agonists.<br/>To date, several ERb agonists have been developed (e.g. DPN, 70-fold selective). The research presented herein, focus towards the design of two types of ERb selective dihydroxyl analogues based on phenolic and cycloheptane hydroxymethyl core. ERb agonist potency was initially evaluated a TR-FRET assay; and compounds having higher potency were re-evaluated in cell based assays for potency and with ERb vs. ERa selectivity. The lead compound thus obtained was further tested for CYP450s metabolism and its <i>in vivo</i> efficiency was evaluated using ovariectomized mice with object recognition (OR) and object placement (OP) tasks.<br/>

Design of ER beta selective agonists for hippocampal memory enhancements

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.