Neurochemistry of Drug Abuse

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DESCRIPTION (provided by applicant): Knowledge of the structure and mechanism of the dopamine transporter is an important step in understanding this key membrane bound protein in dopaminergic neurotransmission. While dopamine and the related neurotransmitters norepinephrine and serotonin are implicated in several mental disorders with severe social impact, the structure and mechanism of the key proteins involved in their signaling remain elusive. One example for the application of such knowledge is the development of medications to treat cocaine abuse, an important goal in addressing the national problem of drug abuse. In order to develop new drugs which prevent the binding of cocaine to its target, the dopamine transporter, it would be very useful to know where both cocaine and dopamine bind on the transporter protein. One approach to localization of the binding site for cocaine has been to explore the structural features of cocaine analogs that affect binding to the transporter. An extension of this approach has been to develop inhibitors which bind irreversibly to the transporter. This class of compounds reacts with the protein to form a covalent bond between the inhibitor and the protein. Knowledge of where this bond is formed, that is, which amino acid in the sequence is involved, allows the binding site to begin to be localized. Mutagenesis studies can then further probe the region. With a range of irreversible inhibitors, including irreversible cocaine analogs, a map of the cocaine binding site can be constructed. To identify the substrate binding region, analogs of the substrate dopamine, will be used that irreversibly react with the transporter. Thus regions important in both inhibition and transport will be identified. The combined results will help to construct a picture of the ligand binding regions critical for human dopamine transporter function and inhibition. Without adequate structural information, it is not possible to understand the mechanism of this important membrane bound protein when functioning normally or in response to acute or chronic drugs of abuse. Identification of domains, and residues within domains, involved in substrate and inhibitor binding is an important first step in understanding the mechanism of this and related transporters.