title: Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-methylphenyl)n ortropane as a selective and potent inhibitor of the neuronal dopamine transporter.
abstract: The pharmacological properties of the iodinated derivative of cocaine (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-me thylphenyl)nortropane (PE2I) were evaluated in vitro in the rat. Binding experiments on rat striatal membranes showed that PE2I selectively recognized the dopamine transporter (DAT) according to a single binding site model with high affinity (K(d) = 4 nM, B(max) = 12 pmol/mg protein). In the cortical membranes, the binding of PE2I was also selectively associated with the DAT (IC(50) for GBR 12909 = 6 nM versus more than 1000 nM for paroxetine), with similar affinity to that of the striatum. Autoradiographic experiments on rat brain sections with [(125)I]PE2I were in agreement with the localization of the DAT. In addition, PE2I was shown to be a potent inhibitor of dopamine uptake, with IC(50) values similar to those for GBR 12909 and 2beta-carbomethoxy-3beta-(4'-iodophenyl)-tropane (beta-CIT) (2-6 nM). All of these findings, combined with previously published data, support the use of PE2I as a selective and potent tool to study the DAT both in vivo and in vitro.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France. chalon@univ-tours.fr
authors.forename: S
authors.initials: S
authors.lastname: Chalon
authors.forename: L
authors.initials: L
authors.lastname: Garreau
authors.forename: P
authors.initials: P
authors.lastname: Emond
authors.forename: L
authors.initials: L
authors.lastname: Zimmer
authors.forename: M P
authors.initials: MP
authors.lastname: Vilar
authors.forename: J C
authors.initials: JC
authors.lastname: Besnard
authors.forename: D
authors.initials: D
authors.lastname: Guilloteau
mesh_terms: D000818:Animals; D001345:Autoradiography; D001693:Biological Transport, Active / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D004298:Dopamine / Q000493:pharmacokinetics*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D009662:Nortropanes / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014793:Visual Cortex / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; C113010:N-(3-iodoprop-2-enyl)-2-beta-carbomethoxy-3-(4-methylphenyl)nortropane; D009662:Nortropanes; D010879:Piperazines; D019275:Radiopharmaceuticals; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine