Pharmacological Characterization of (E)-N-(3-iodoprop-2-enyl)-2β-Carbomethoxy-3β-(4′-methylphenyl)nortropane as a Selective and Potent Inhibitor of the Neuronal Dopamine Transporter1

  1. Sylvie Chalon,
  2. Lucette Garreau,
  3. Patrick Emond,
  4. Luc Zimmer,
  5. Marie-Paule Vilar,
  6. Jean-Claude Besnard and
  7. Denis Guilloteau
  1. Institut National de la Sante et de la Recherche Medicale U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France

    Abstract

    The pharmacological properties of the iodinated derivative of cocaine (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)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 (Kd = 4 nM,Bmax = 12 pmol/mg protein). In the cortical membranes, the binding of PE2I was also selectively associated with the DAT (IC50 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 [125I]PE2I were in agreement with the localization of the DAT. In addition, PE2I was shown to be a potent inhibitor of dopamine uptake, with IC50 values similar to those for GBR 12909 and 2β-carbomethoxy-3β-(4′-iodophenyl)-tropane (β-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.

    Footnotes

    • Send reprint requests to: Dr. Sylvie Chalon, INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Faculté de Pharmacie, 31 avenue Monge, 37200 Tours, France. E-mail: chalon{at}univ-tours.fr

    • ↵1 This work was supported by Institut National de la Sante et de la Recherche Medicale, Pôle GBM, and the European program EUREKA.

    • Abbreviations:
      DA
      dopamine
      DAT
      dopamine transporter
      PE2I
      (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-methylphenyl)nortropane
      5-HT
      5-hydroxytryptamine (serotonin)
      NE
      norepinephrine
      SERT
      serotonin transporter
      SPECT
      single-photon emission computed tomography
      β-CIT
      2β-carbomethoxy-3β-(4′-iodophenyl)-tropane
      IPT
      (E)-N-(3-iodoprop-2-enyl)-2β-carbomethoxy-3β-(4′-chlorophenyl)nortropane
      • Received February 15, 1999.
      • Accepted June 25, 1999.
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    1. JPET November 1, 1999 vol. 291 no. 2 648-654
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