Additional studies of BZT analogues are ongoing combining molecular and behavioral techniques with the most interesting of the BZT analogues that we have discovered over the years. These studies are directed at the identification and characterization of the DAT binding domains of the BZT analogues in comparison to those for cocaine-like drugs to better understand what contributes to the different behavioral effects of the compounds. Studies addressing association rate and conformational equilibrium of the DAT with BZT analogues, along lines described above, will be important for the testing of various hypotheses regarding mechanisms accounting for the behavioral effects of these compounds.
As has been demonstrated, the BZT analogues are bioavailable, readily penetrate the blood brain barrier and gain high levels of brain to plasma ratios within minutes of injection. Nevertheless, DAT occupancy and subsequent increases in DA, measured by microdialysis, are significantly delayed as compared to cocaine. Further, DAT occupancy and elevated levels of DA are also long lasting. All of these features appear to be important for the lack of abuse liability of the BZT analogues, and their potential as treatments for cocaine abuse.
Future investigations will continue to elucidate the interactions of these drugs in comparison to cocaine at the DAT and to reveal how those differences affect other neural systems and circuitry, so as to provide a better understanding of cocaine's mechanism of action and to feed this information into our drug design. Further, as the BZT analogues do not appear to have significant abuse liability they may also have therapeutic utility in other disorders such as ADHD and obesity, areas in which drug development is an emerging line of investigation.
Acknowledgements We would like to acknowledge the dedicated members of our laboratories, past and present, who have diligently taken on the arduous tasks of synthesizing, characterizing and biologically evaluating all of our novel compounds. We are particularly indebted to Theresa Kopajtic who has performed the vast majority of the in vitro studies on these compounds and has helped in uncountable ways. The authors also acknowledge support from Dr. Jane Acri and Dr. Carol Hubner, NIDA Addiction Treatment Discovery Program, Division of Pharmacotherapies and Medical Consequences of Drug Abuse, NIDA, and data obtained through contract N01DA-6-8062. This work was supported by the National Institute on Drug Abuse - Intramural Research Program.
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