Competition by monophenolic estrogens and catecholestrogens for high-affinity uptake of [3H](-)-norepinephrine into...

High affinity uptake of [3H](-)-norepinephrine (NE) was investigated in synaptosomes from rat cerebral cortex (Km = 360 +/- 30 nM) and hypothalamus (Km = 307 +/- 90 nM). Estrogens but not androgens, glucocorticoids or progestin interfered competitively with NE uptake. Ethinylestradiol was the most effective competitor tested, its Ki value being 200 nM in the cortex and 144 nM in the hypothalamus. Stereospecificity of the inhibitory effect of estradiol-17 beta with a preference for the 17 beta-hydroxy group was indicated by the ineffectiveness of estradiol-17 alpha and estrone as competitors. A-ring substitution of estradiol-17 beta 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 11 beta completely abolished the competitive action of estradiol-17 beta or ethinylestradiol on NE uptake.