title: Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters.
abstract: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06510.
authors.forename: S
authors.initials: S
authors.lastname: Schuldiner
authors.forename: S
authors.initials: S
authors.lastname: Steiner-Mordoch
authors.forename: R
authors.initials: R
authors.lastname: Yelin
authors.forename: S C
authors.initials: SC
authors.lastname: Wall
authors.forename: G
authors.initials: G
authors.lastname: Rudnick
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects*; D002417:Cattle; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002837:Chromaffin Granules / Q000187:drug effects / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000187:drug effects*; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009419:Nerve Tissue Proteins; D012110:Reserpine / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D010133:p-Chloroamphetamine / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D005277:Fenfluramine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D010133:p-Chloroamphetamine; D012110:Reserpine; D018817:N-Methyl-3,4-methylenedioxyamphetamine