Identification of effective pharmacotherapeutic agents continues to be a major challenge in the treatment of cocaine abuse. The high abuse potential of cocaine is believed to be in part due to its rapid onset and short duration of action which directly correlates with its pharmacokinetic (PK) and pharmacodynamic (PD) properties. This suggests that a PK and PD profile different from cocaine would be desired characteristic for a substitute therapeutic agent. Agents developed based on the 'substitute therapy approach' bind to the dopamine transporter (DAT), inhibit dopamine (DA) reuptake, and prolong DA levels to a lesser extent than cocaine. As such, their BBB transport, distribution and disposition of a substitute therapeutic agent should reflect the so-called rate hypothesis of psychoactive drug effect. This means that they should display a slow input into the systemic circulation and slow clearance from the body. The BZT analogs, DA uptake inhibitors, bind with higher affinity to the DAT, but are not efficacious locomotor stimulants. In preliminary studies, select BZT analogs display high permeability across the BBB, a slow disposition and a long duration of DA elevation in comparison to cocaine. From these studies, it appears that the BZT analog structure and physiochemical properties are determining factors in their BBB transport, disposition and DA elevation. As such, our central hypothesis is that the BBB transport, PK and PD of the BZT analogs, is dependent on their structural modifications (e.g., substitution, enantiomer status, lipophilcity, etc) and resultant physiochemical properties. To examine this hypothesis, the following specific aims will be pursued: SA1. Determine the BBB permeability of BZT analogs by examining structural and physiochemical differences using BBMECs. SA2 Characterize the brain uptake and PK of BZT analogs after IV and oral dosing to rats. SA 3: Characterize the PD (e.g, dopamine release) of the BZT analogs and cocaine after IV and oral dosing to rats using microdialysis. SA 4. Characterize the PK and PD interaction of select BZT analogs and cocaine after IV and oral dosing. These studies are essential to the further evaluation of substitute therapeutics and will elucidate the structural related features that are important in the BBB transport, PK and associated PD characteristics required for effective pharmacotherapy for cocaine abuse.
