There is an urgent need for the development of a medication to treat addiction to cocaine, a major drug of abuse. The reinforcing effect of cocaine is believed to originate mainly from its binding to the dopamine transporter (DAT) in the brain. However, involvement of serotonergic neurotransmission has also been implicated in the manifestation of cocaine's behavioral effects. A great number of structurally diverse compounds have been developed for the DAT for potential development of cocaine medications. However, these efforts have met with limited success so far. One other shortcoming which affect most of the DAT-blockers developed so far is their inherent activity for the norepinephrine transporter (NET) which is readily apparent when uptake inhibitory activity is measured rather than binding potency. In our effort to contribute towards developing medications for cocaine addiction, we have synthesized a number of potent and selective molecules for the DAT. However, some of these molecules, in spite of their potent in vitro activity, were only weakly active in vivo. In order to bestow better pharmacodynamic and pharmcokinetic properties to these molecules, three major structural modifications were introduced in the previous funding cycle. These changes involved introduction of rigidity in our original flexible parent molecules and introduction of an additional functionality in the central piperidine ring. These structural alterations resulted in high potency and better selectivity at DAT, and much higher in vivo activity compared to the original flexible parent molecules. One of the lead compounds developed from these SAR studies decreased self-administration of cocaine in rhesus monkey trained to lever press for both food and cocaine, indicating its potential application in substitution therapy. In the next phase of the project, we propose to carry out comprehensive SAR studies in these three series of drugs aiming at compounds that have the ability either to replace cocaine effectively for long-term abstinence or to prevent relapse. Our proposal is focused on the dopaminergic aspect of the activity of cocaine. However, we also plan to synthesize compounds with variable degree of serotonin transporter (SERT) activity to address the complex issue of the involvement of serotonin in the mechanism of action of cocaine. Compounds will be characterized in monoamine transporters uptake and binding assays to evaluate their in vitro activity. Compounds selected based on their in vitro activity will be tested for effects on locomotor activity and drug discrimination and self-administration studies to assess their potential in replacement therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA012449-06A2
Application #
7033690
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Shih, Ming L
Project Start
1999-09-30
Project End
2008-08-31
Budget Start
2005-09-25
Budget End
2006-08-31
Support Year
6
Fiscal Year
2005
Total Cost
$404,618
Indirect Cost
Name
Wayne State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Pharmacy
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
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Reith, Maarten E A; Wang, Lijuan C; Dutta, Aloke K (2005) Pharmacological profile of radioligand binding to the norepinephrine transporter: instances of poor indication of functional activity. J Neurosci Methods 143:87-94
Kolhatkar, Rohit; Cook, Charles D; Ghorai, Sujit K et al. (2004) Further structurally constrained analogues of cis-(6-benzhydrylpiperidin-3-yl)benzylamine with elucidation of bioactive conformation: discovery of 1,4-diazabicyclo[3.3.1]nonane derivatives and evaluation of their biological properties for the monoamine tr J Med Chem 47:5101-13
Zhen, Juan; Maiti, Soumen; Chen, Nianhang et al. (2004) Interaction between a hydroxypiperidine analogue of 4-(2-benzhydryloxy-ethyl)-1-(4-fluorobenzyl)piperidine and Aspartate 68 in the human dopamine transporter. Eur J Pharmacol 506:17-26

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