Structure-activity relationships for the reserpine-like actions of derivatives of β-carboline in vitro
The abilities of 10 derivatives of β-carboline to competitively inhibit the ATP-Mg2+ stimulated uptake of epinephrine (0.1 mM) were studied in isolated rat adrenal medullary storage vesicles. Uptake was inhibited 72% by harmine (0.03 mM), 64% by harmaline, 59% by 2-methylharmine, 43% by harmol and 25% by harman. Norharman, 6-methoxyharman, 6-methoxyindole, 6-methoxytetrahydroharman and yohimbine did not inhibit epinephrine uptake, nor did any of the 10 derivatives affect metaraminol uptake. The potencies of epinephrine uptake inhibitors were unrelated to the lipid solubility or pK of the drugs, suggesting that differences in activity reflected differences in affinity for the catecholamine transport site. Harmol, 2-methylharmine and harmaline were themselves incorporated into the vesicles, but the temperature dependence was much smaller than that of epinephrine or metaraminol (Q30 of 1.5-2 vs. 4.5-7). These data suggest that β-carboline derivatives interact with a catecholamine carrier on the outside surface of the vesicle membrane and that the attachment involves at least 3 portions of the molecule. The different structure- activity relationships for inhibition of epinephrine uptake vs. uptake of the β-carboline derivatives themselves indicate that two separate processes, inward transport and subsequent intravesicular binding, contribute to the measured uptake. © 1974.
Volume / Issue
Start / End Page
International Standard Serial Number (ISSN)
Digital Object Identifier (DOI)