Exploiting nongenomic estrogen receptor-mediated signaling for the Development of pathway-selective Estrogen receptor ligands.

Abstract

Different molecular mechanisms mediate the diverse biological effects of estrogens. The classical genomic mechanism is based on the function of the ER as a ligand-dependent transcription factor that binds to estrogen-response elements (EREs) in promoters of target genes to initiate gene expression. These direct genomic effects play a prominent role in the regulation of reproductive function. In contrast, nongenomic effects mediated by the classical ER have been demonstrated to activate PI3K, leading to the activation of endothelial NOS (eNOS) and hence vasorelaxation. Pathway-selective ER ligands might represent a novel option for hormone replacement therapy. Here we describe the identification and in vitro characterization of tool compounds that bind the ER reasonably well but exhibit low transcriptional activity on ERE-driven promoters. However, these compounds behave as potent stimulators of PI3K/Akt activation in vitro and lead to aortic vessel relaxation, a mechanism that is thought to be driven by nongenomic ER action. In a second set of experiments, we analyze how the in vitro pathway selectivity translates into the in vivo situation. We examine our tool compounds in comparison to estradiol and estren in the following paradigms: bone protection, uterine growth assays, and mammary gland assays.