Competition by monophenolic estrogens and catecholestrogens for high-affinity uptake of [H](−)-norepinephrine into synaptosomes from rat cerebral cortex and hypothalamus

High affinity uptake of [³H](−)-norepinephrine (NE) was investigated in synaptosomes from rat cerebral cortex (K_m=360±30nM) and hypothalamus (K_m=307±90nM). Estrogens but not androgens, glucocorticoids or progestin interfered competitively with NE uptake. Ethinylestradiol was the most effective competitor tested, its K_i value being 200 nM in the cortex and 144 nM in the hypothalamus. Stereospecificity of the inhibitory effect of estradiol-17β with a preference for the 17β-hydroxy group was indicated by the ineffectiveness of estradiol-17α and estrone as competitors. A-ring substitution of estradiol-17β or ethinylestradiol by hydroxyl groups in positions 2 and 4 (yielding catecholestrogens) or methyl substitution in positions 2 and 4 (yielding methylestrogens) significantly reduced the inhibitory potency of the estrogen. Methoxylation in positions 2,4 or 11β completely abolished the competitive action of estradiol-17β or ethinylestradiol on NE uptake.