Cocaine abuse and dependence is a substantial public health threat in the United States and around the world. The widespread use of cocaine and other psychostimulants has stimulated extensive efforts to develop treatment programs for this type of addiction. One of the top priorities of the National Institute on Drug Abuse is to find a medication to reduce the effects of cocaine and to use this medication as one part of a comprehensive treatment program. The objective of this research proposal is to synthesize and test drugs that may aid in the fight against addiction to cocaine, amphetamines and other stimulants. Cocaine analogs, called tropanes, have been studied extensively. These drugs have high potency for blocking the dopamine transporter and last a long time, which is desirable for a therapeutic drug, but they are also self-administered by animals, and this ability to be reinforcing makes them less desirable. Removal of the two-carbon bridge of these tropanes gives rise to piperidines. Some piperidines have been shown to act as dopamine reuptake inhibitors without being reinforcing, or addictive. Thus, the central hypothesis of this proposal is that piperidine derivatives of cocaine analogs will be high potency inhibitors of the dopamine transporter (DAT) and the serotonin transporter. It is proposed that piperidine derivatives of tropanes reported to have high affinities for the dopamine transporter (DAT) and serotonin transporter (SERT or 5-HTT) will serve as excellent leads for medication development. The synthesis will be accomplished using established pathways and allows for easy entry and purification of all compounds. In vitro testing will include determination of IC50 and Ki values for all piperidines synthesized and thcir DAT/5-HT selectivity values. In addition, the ability of the new compounds to prevent induced monoamine release following methamphetamine application in vitro will be determined. Finally, in vivo behavioral place preference studies will be performed with the compounds to assess their reinforcing properties. The long-range goal of the project is to submit compounds that have appropriate profiles and lack abuse potential to the NIDA Division of Treatment Research and Development for further consideration as potential therapeutic agents for cocaine addiction.
