The AAPS Journal

, Volume 8, Issue 1, pp E196–E203

Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse

  • F. Ivy Carroll
  • James L. Howard
  • Leonard L. Howell
  • Barbara S. Fox
  • Michael J. Kuhar
Article

Abstract

The discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacotherapies for treating cocaine addiction are presented. The studies are based on the hypothesis that a dopamine reuptake inhibitor is expected to partially substitute for cocaine, thus decreasing cocaine self-administration and minimizing the craving for cocaine. This type of indirect agonist therapy has been highly effective for treating smoking addiction (nicotine replacement therapy) and heroin addiction (methadone). To be an effective pharmacotherapy for cocaine addiction, the potential drug must be safe, long-acting, and have minimal abuse potential. We have developed several 3-phenyltropane analogs that are potent dopamine uptake inhibitors, and some are selective for the dopamine transporter relative to the serotonin and norepinephrine transporters. In animal studies, these compounds substitute for cocaine, reduce the intake of cocaine in rats and rhesus monkeys trained to self-administer cocaine, and have demonstrated a slow onset and long duration of action and lack of sensitization. The 3-phenyltropane analogs were also tested in a rhesus monkey self-administration model to define their abuse potential relative to cocaine. Based on these studies, 3β-(4-chlorophenyl)-2β-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected for preclinical development.

Keywords

RTI-336 dopamine transporter cocaine abuse pharmacotherapy 3-aryltropanes 

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Copyright information

© American Association of Pharmaceutical Scientists 2006

Authors and Affiliations

  • F. Ivy Carroll
    • 1
  • James L. Howard
    • 2
  • Leonard L. Howell
    • 3
  • Barbara S. Fox
    • 4
  • Michael J. Kuhar
    • 3
  1. 1.Center for Organic and Medicinal ChemistryResearch Triangle InstituteResearch Triangle Park
  2. 2.Howard AssociatesLLCResearch Triangle Park
  3. 3.Yerkes Regional Primate Research CenterEmory UniversityAtlanta
  4. 4.Addiction Therapies IncWayland

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