Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse

The discovery and preclinical development of selective dopamine reuptake inhibitors as potential pharmacothera-pies for treating cocaine addiction are presented. The studies are based on the hypothesis that a dopamine reuptake inhibi-tor 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 (nico-tine replacement therapy) and heroin addiction (methadone). To be an effective pharmacotherapy for cocaine addiction, the potential drug must be safe, long-acting, and have mini-mal abuse potential. We have developed several 3-phenyl-tropane 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-phen-yltropane analogs were also tested in a rhesus monkey self-administration model to defi ne their abuse potential relative to cocaine. Based on these studies, 3 -(4-chlorophenyl)-2 -[3-(4 ’-methylphenyl)isoxazol-5-yl]tropane (RTI-336) has been selected for preclinical development. K EYWORDS: RTI-336, dopamine transporter, cocaine abuse, pharmacotherapy, 3-aryltropane