Critical to understanding the mechanism of cocaine addiction is delineation of the role of dopamine reuptake inhibition in reinforcement which leads to repeated self-administration. This proposal outlines the preparation of novel tropane and 3- arylindan dopamine reuptake inhibitors as slow-release prodrugs designed with a range of different specificities and potencies. These compounds will be used to explore the effects rate-of-onset and duration-of-action have on cocaine self-administration, locomotor activity and cocaine dose-response curves in animal models. The tropane and 3-aryl-1 substituted indan structures described are designed based on well understood pharmacophore properties of monoamine binding sites in brain tissue and are prepared readily by known chemistry. Development of novel compounds will be guided by close collaboration with David Roberts, Steven Childers and others at the Center for Neurobiological Investigation of Drug Abuse at the Bowman Gray School of Medicine, Wake Forest University, where assays of monoamine transporter binding and behavioral effects of long-term prodrug treatment will be performed.
