Synthesis and biological evaluation of SERMs with potent nongenomic estrogenic activity

We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERα and ERβ). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic γ-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.