Neuroprotective effects of estratriene analogs: Structure-activity relationships and molecular optimization

Estrogens are neuroprotectants against a variety of insults, both in vitro and in vivo. Many of these insults involve an oxidative stress component and estrogens are known antioxidants. We (Green et al. [1997b] J Steroid Biochem Mol Biol 63:229-235) and others (Behl et al. [1997] Mol Pharmacol 51:535-541; Moosmann and Behl [1999] Proc Natl Acad Sci USA 96:8867-8872) have determined that the phenolic nature of the A-ring of the estradiol molecule is essential for neuroprotection. We performed structure-activity relationship studies using a library of estratriene compounds in well-established in vitro models for neuroprotection. We tested over 70 compounds in HT-22 (murine hippocampal) cells for their ability to inhibit cell toxicity against glutamate and iodoacetic acid, at two doses for each insult, and determined EC₅₀ values to ascertain potency comparisons with 17β-estradiol (E2). We verified that a phenolic A ring was essential for neuroprotection in these models. We also observed that hydrophobicity and planarity affects the ability of estratrienes to protect cells from oxidative stress. This neuroprotection correlated with their ability to inhibit iron-induced lipid peroxidation in vitro. In contrast, the ability of these estratrienes to bind estrogen receptors was negatively correlated with their ability to protect cells from oxidative stress or inhibit lipid peroxidation.