COMBINATORIAL PHARMACOTHERAPIES FOR COCAINE DEPENDENCE

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DESCRIPTION: (Applicant's Abstract) Cocaine overuse in the United States has resulted in enormous social and economic loss. Clinicians have attempted to use pharmacological intervention to decrease cocaine craving by blocking the affects of the "sympathetic neural storm", but the ideal pharmacotherapy has not been developed and design and synthesis of new medications designed specifically for the purpose of treating cocaine abuse is urgently needed. Because the dopamine transporter (DAT) has been identified as the relevant macromolecule for initiating cocaine self-administration, development of novel approaches to design, synthesize and procure high affinity antagonists (or partial agonists) of the DAT that do not inhibit dopamine uptake and/or that stimulate dopamine uptake would constitute an important new pharmacotherapy in the medical treatment of cocaine abuse. Such a medication could be very helpful to a cocaine addict if administered by a doctor to a patient also undergoing psychological counseling. To obtain such a human therapeutic will require the screening of large numbers of potential DAT antagonists (or partial antagonist). The long term goal of our research is to develop selective, nontoxic high affinity antagonists (or partial antagonists) of the human dopamine transporter with long duration of action that blocks the reinforcing and stimulant properties of cocaine. The proposed studies are divided into four major sections: 1) Design and synthesis of directed organic chemical combinatorial libraries and synthesis of directed pseudopeptide combinatorial libraries, 2) Evaluation of the directed combinatorial libraries as antagonists (or partial agonists) of the cDNA-expressed human hDAT as well as in uptake inhibition experiments, 3) Further define the active compounds identified in section 1 and 2, and 4) Evaluation of the selectivity of the antagonists for the hDAT relative to the norepinephrine and serotonin transporter, and examine key pharmaceutical and pharmacokinetic properties of the "optimized" compounds. The specific aims of section 2 include the kinetic evaluation of the libraries by screening for hDAT binding and dopamine uptake. The specific aims of section 4 include the large scale synthesis of the optimized drug candidates, screening against other transporter and testing the pharmaceutical properties of the most active compounds. Animal behavioral assessment may predict in vivo efficacy. The study will provide an understanding of the structural and pharmaceutical properties of hDAT antagonists. The work will lead to new insight into the preparation of human medications necessary in the cessation of cocaine abuse.