Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters
Schuldiner, S.; Steiner-Mordoch, S.; Yelin, R.; Wall, S.C.; Rudnick, G.
Molecular Pharmacology 44(6): 1227-1231
1993
ISSN/ISBN: 0026-895X PMID: 7903417 Document Number: 415133
The interaction of fenfluramine, 3,4-methylenedioxymethamphetamine (MDMA), and p-chloroamphetamine (PCA) with the platelet plasma membrane serotonin transporter and the vesicular amine transporter were studied using both transport and binding measurements. Fenfluramine is apparently a substrate for the plasma membrane transporter, and consequently inhibits both serotonin transport and imipramine binding. Moreover, fenfluramine exchanges with internal (3H)serotonin in a plasma membrane transporter-mediated reaction that requires NaCl and is blocked by imipramine. These properties are similar to those of MDMA and PCA as previously described. In adrenal chromaffin granule membrane vesicles containing the vesicular amine transporter, fenfluramine inhibited serotonin transport and dissipated the transmembrane pH difference (DELTA-pH) that drives amine uptake. The use of (3H)reserpine-binding measurements to determine drug interaction with the vesicular amine transporter allowed assessment of the relative ability of MDMA, PCA, and fenfluramine to bind to the substrate site of the vesicular transporter. These measurements permit a distinction between inhibition of vesicular serotonin transport by directly blocking vesicular amine transport and by dissipating DELTA-pH. The results indicate that MDMA and fenfluramine inhibit by both mechanisms but PCA dissipates DELTA-pH without blocking vesicular amine transport directly.