The objective of this proposal is the rational design and synthesis of cocaine analogs that bind to the cocaine recognition site on the dopamine transporter but fail to inhibit or only weakly inhibit the reuptake of dopamine. Such antagonists or partial agonists are of great therapeutic potential (1) for the treatment of some of the adverse side effects associated with cocaine overdose, or (2) for the maintenance of addicts in treatment programs. To achieve these goals it is essential to have an increased understanding of the basic chemistry and pharmacology of cocaine.
The specific aim of this program is to synthesize carefully selected analogs of cocaine to obtain a more complete understanding of the structure activity relations that govern cocaine's pharmacology. Specifically, this proposal centers around the synthesis of rigid cocaine analogs with a """"""""locked"""""""" conformation of the nitrogen lone pair to address the importance of the directionality in the binding of cocaine to its recognition site. Additional analogs will be prepared to further probe the importance of interactions between cocaine's nitrogen and dopamine transporter. Molecular modeling and biological data on the compounds prepared will be used to further develop a pharmacophore model. This will be accomplished with an eye toward identifying any structural modifications that increase binding while decreasing or eliminating dopamine uptake inhibition.
