This grant application is the molecular pharmacology portion of an Investigator Initiated Interactive Research Project designed to identify pharmacotherapeutic agents that can be used in the treatment of cocaine addiction. The strategy of this research initiative is three-fold. I. Medicinal Chemistry: A panel of 50-75 novel benzamide derivatives of 2,3-dimethoxy-N-(p-flurobenzyl)piperdin-4-yl benzamide (MBP) and 2,3 - dimethoxy-N-(9-p-flurobenzyl)-azabicyclo[3.3.1]nonan-3beta-yl benzarnide (MABN), which are known to be high-affinity, nonselective antagonists for D2 and D3 receptors, will be synthesized. ll. Pharmacology: Genetically engineered eukayotic cells, expressing high levels of D2-like dopamine (D2, D3 and D4) receptors, will be used to characterize the pharmacologic selectivity of each benzamide derivative for the three D2-like dopamine receptor subtypes. Ill. Behavioral Studies: Those benzamide derivatives exhibiting the greatest selectivity will be used 1) to determine their efficacy for antagonizing the reinforcing effects of cocaine self-administration in primates using behavioral paradigms, 2) to investigate the molecular properties of the D2-like neurotransmitter binding sites using affinity labeling techniques, and 3) to explore the potential for using receptor subtype selective irreversible antagonists as a therapeutic tools for drug abuse rehabilitation. Although cocaine's reinforcing effects are known to be mediated through dopamine neurotransmission, it is not clear which of the dopamine receptor subtypes play a predominant role in reinforcement. One obstacle to defining which dopamine receptor subtype(s) are involved in reinforcing effects is the lack of high-affinity, selective antagonists for each of the receptor subtypes. The experimental strategy for this proposal is to 1) develop a genetically engineered recombinant baculovirus virus that can be used to infect Sf9 cells for the expression of D2, D3 and D4 receptors, 2) use radioligand binding techniques to define the pharmacologic selectivity of a panel of novel benzamides for D2, D3 and D4 receptors expressed in Sf9 cells, and 3) prepare and characterize affinity labeling reagents that can be used a) in concert with dopamine receptor subtypes expressed in Sf9 cells to determine the position and orientation of benzamides within the neurotransmitter binding sites of D2, D3 and D4 dopamine receptors, and b) to explore the feasibility of using irreversible receptor blocking agents as a therapeutic tool in the treatment in cocaine abuse.
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