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


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.


RTI-336 dopamine transporter cocaine abuse pharmacotherapy 3-aryltropanes 


  1. 1.
    Substance Abuse and Mental Health Services Administration.200 National Survey on Drug Use and Health. Washington, DC: Department of Health and Human Services; 2003.Google Scholar
  2. 2.
    Substance Abuse and Mental Health Services Administration.Drug Abuse Warning Network (DAWN) Publications (1994–2002). Washington, DC: Department of Health and Human Services; 2004.Google Scholar
  3. 3.
    Carroll FI, Howell LL, Kuhar MJ. Pharmacotherapies for treatment of cocaine abuse: preclinical aspects.J Med Chem. 1999;42:2721–2736.CrossRefPubMedGoogle Scholar
  4. 4.
    Howell LL, Wilcox KM. The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates.J Pharmacol Exp Ther. 2001298:1–6.PubMedGoogle Scholar
  5. 5.
    Newman AH, Kulkarni S. Probes for the dopamine transporter: new leads toward a cocaine-abuse therapeutic: a focus on analogues of benztropine and rimcazole.Med Res Rev. 2002;22:429–464.CrossRefPubMedGoogle Scholar
  6. 6.
    Carrera MR, Meijler MM, Janda KD. Cocaine pharmacology and current pharmacotherapies for its abuse.Bioorg Med Chem. 2004;12:5019–5030.CrossRefPubMedGoogle Scholar
  7. 7.
    Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ. Cocaine receptors on dopamine transporters are related to self-administration of cocaine.Science. 1987;237:1219–1223.CrossRefPubMedGoogle Scholar
  8. 8.
    Bergman J, Madras BK, Johnson SE, Spealman RD. Effects of cocaine and related drugs in nonhuman primates. III. Self-administration by squirrel monkeys.J Pharmacol Exp Ther. 1989;251:150–155.PubMedGoogle Scholar
  9. 9.
    Kuhar MJ, Ritz MC, Boja JW. The dopamine hypothesis of the reinforcing properties of cocaine.Trends Neurosci. 1991;14:299–302.CrossRefPubMedGoogle Scholar
  10. 10.
    Wise RA Jr, Newton P Jr, Leeb K Jr, Burnette B Jr, Pocock D Jr, Justice JB Jr. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats.Psychopharmacology (Berl) 1995;120:10–20.CrossRefGoogle Scholar
  11. 11.
    Wilcox KM, Rowlett JK, Paul IA, Ordway GA, Woolverton WL. On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.,Psychopharmacology (Berl). 2000;153:139–147.CrossRefGoogle Scholar
  12. 12.
    Carroll FI. 2002 Medicinal Chemistry Division Award address: monoamine transporters and opioid receptors. Targets for addiction therapy.J Med Chem. 2003;46:1775–1794.CrossRefPubMedGoogle Scholar
  13. 13.
    Carroll FI, Runyon SP, Abraham P, et al. Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers.J Med Chem. 2004;47:6401–6409.CrossRefPubMedGoogle Scholar
  14. 14.
    Balster RL, Carroll FI, Graham JH, et al. Potent substituted-3b-phenyltropane analogs of cocaine have cocaine-like discriminative stimulus effects.Drug Alcohol Depend. 1991;29:145–151.CrossRefPubMedGoogle Scholar
  15. 15.
    Fleckenstein AE, Kopajtic TA, Boja JW, Carroll FI, Kuhar MJ. Highly potent cocaine analogs cause long-lasting increases in locomotor activity.Eur J Pharmacol. 1996;311:109–114.CrossRefPubMedGoogle Scholar
  16. 16.
    Fowler JS, Volkow ND, Logan J, et al. Measuring dopamine transporter occupancy by cocaine in vivo: radiotracer considerations.Synapse. 1998;28:111–116.CrossRefPubMedGoogle Scholar
  17. 17.
    Volkow ND, Wang GJ, Fischman MW, et al. Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain.Life Sci. 2000;67:1507–1515.CrossRefPubMedGoogle Scholar
  18. 18.
    Zernig G, Giacomuzzi S, Riemer Y, Wakonigg G, Sturm K, Saria A. Intravenous drug injection habits: drug user's self-reports versus researchers' perception.Pharmacology. 2003;68:49–56.CrossRefPubMedGoogle Scholar
  19. 19.
    Balster RL, Schuster CR. Fixed-interval schedule of cocaine reinforcement: effect of dose and infusion duration.J Exp Anal Behav. 1973;20:119–129.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Woolverton WL, Wang Z. Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine.Eur J Pharmacol. 2004;486:251–257.CrossRefPubMedGoogle Scholar
  21. 21.
    Lile JA, Morgan D, Birmingham AM, et al. The reinforcing efficacy of the dopamine reuptake inhibitor 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) as measured by a progressive-ratio schedule and a choice procedure in rhesus monkeys.J Pharmacol Exp Ther. 2002;303:640–648.CrossRefPubMedGoogle Scholar
  22. 22.
    Woolverton WL, Ranaldi R, Wang Z, et al. Reinforcing strength of a novel dopamine transporter ligand: pharmacodynamic and pharmacokinetic mechanisms.J Pharmacol Exp Ther. 2002;303;211–217.CrossRefPubMedGoogle Scholar
  23. 23.
    Samaha AN, Robinson TE. Why does the rapid delivery of drugs to the brain promote addiction?Trends Pharmacol Sci. 2005;26:82–87.CrossRefPubMedGoogle Scholar
  24. 24.
    Volkow ND, Fowler JS, Wang GJ, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications.Mol Psychiatry. 2004;9:557–569.CrossRefPubMedGoogle Scholar
  25. 25.
    Carroll FI, Pawlush N, Kuhar MJ, Pollard GT, Howard JL. Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes.J Med Chem. 2004;47:296–302.CrossRefPubMedGoogle Scholar
  26. 26.
    Lindsey KP, Wilcox KM, Votaw JR, et al. Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.J Pharmacol Exp Ther. 2004;309:959–969.CrossRefPubMedGoogle Scholar

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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