Synthesis of Novel Agents for use in Addiction Treatment

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DESCRIPTION (provided by applicant): Drug addiction is a widespread problem of increasing concern in the United States. Sharing injection drug works such as needles or syringes with someone who is HIV positive is the second-most-common way of contracting HIV among both black men and black women. The most common way of transmission for both groups is through unprotected sex with a man who has HIV. Because drug use and particularly methamphetamine use, which is on the increase among African-Americans is often associated with higher incidence of unprotected sex, then it can be reasoned that an appropriate strategy for fighting HIV transmission is to treat drug addiction. Post-mortem studies of drug addicts indicate elevated levels of D3 receptors in the mesolimbic regions of the brain responsible for feelings of reward and pleasure. The concentration of dopamine D3 receptors is significantly greater than that of dopamine D2 receptors in the mesolimbic regions supporting the conclusion that D3 receptors may be critical targets for effective therapeutic intervention to assist in treating addiction. The density of D3, not D2 receptors was observed to be elevated in off-treatment psychotic patients. Additionally, similar increases were observed in individuals chronically exposed to cocaine, known to aggravate and precipitate psychotic states. Medication to improve cognitive skills, reverse impairments, as well as address the resultant psychosis experienced as a consequence of addiction to drugs is a priority for successful rehabilitation therapy. Benzazepine derivatives have been reported to possess anti-depressant properties and are quite useful in the treatment of chronic neurological disorders including brain damage resulting from epilepsy, stroke, Alzheimer's disease, drug abuse and AIDS-related dementia. Our immediate objective in this project is to determine dopamine D1, D2, D3, D4, D5 and serotonin 5-HT receptor binding affinities of novel benzofuro-benzazepine-6-12-dione derivatives. In general, we expect to assist in the development of D3 receptor selective antagonists or partial agonists for use as antipsychotics in the treatment of addiction-related psychosis. The specific aims of this work are to (1) refine a synthetic pathway for production of novel potential D3 receptor selective ligands; (2) determine dopamine D1, D2, D3, D4, D5 and serotonin 5-HT receptor binding affinities of each newly synthesized ligand; (3) Perform functional assays on: a) ligands exhibiting high to modest affinity at serotonin 5-HT receptors and b) ligands exhibiting selectivity and/or good affinity for dopamine receptors D3 and/or D2. The physiological effect of ligands exhibiting selectivity and/or good affinity for dopamine receptors D3 and/or D2 will be evaluated on DA clearance in the nucleus accumbens of rats using voltammetry. The long- term goal of this project is to contribute to a better understanding of the role of D3 receptors in addiction as well as to assist in the development of a therapeutic pharmacophore for central nervous system disorders. PUBLIC HEALTH RELEVANCE: The proposed studies are relevant to the development of dopamine D3 receptor selective medicinal agents for use in the treatment of addiction. The results from this project will contribute significantly to advancements in the area of addiction research and rehabilitation treatment. Overall this research is expected to assist in promoting the mental health of recovering addicts as well as reduce the possibility of relapse.