Development of Dopamine D3 Ligands as Medications for Psychostimulant Addiction

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DESCRIPTION (provided by applicant): Our long-term goal of the proposed research is to develop medications for the treatment of drug addiction. Recent research has provided convincing evidence that compounds that are highly selective for the D3 subtype of dopamine receptors with antagonist or partial agonist properties have the potential of being developed into medications for the treatment of addiction to cocaine, methamphetamine, and related psychostimulants. Proposed herein is a multidisciplinary research involving structure-based rational drug design, synthesis, and evaluations to identify and develop compounds with the potential for becoming clinically useful treatment agents. A major consideration that forms the focus of our research is the development of new ligands and novel scaffolds endowed with binding and functional selectivity for the D3 receptor over other dopamine receptor subtypes and with favorable physicochemical and pharmacokinetic properties for distribution into the central nervous system. Our recent efforts on the design and synthesis of novel ligands of the dopamine D3 receptor has provided us with promising lead compounds that could potentially be optimized through structure-based drug design efforts. The envisioned goals of lead discovery, lead optimization, and identification and selection of candidates for further development are to be achieved through the pursuit of the following specific aims: (1) Design and synthesize new ligands through specific rational modifications to the lead templates on the basis of protein-ligand interactions predicted through ligand docking into the active site of a validated and refined homology model of the dopamine D3 receptor. (2) Develop a D2 receptor model and perform comparative ligand docking studies to gain insight into the structural basis of selectivity between the D3 and D2 receptors and to design new ligands with improved selectivity. (3) Evaluate the binding affinity of the synthesized ligands in vitro against human D3, D2, D4 and D1 receptors using cells expressing each subtype of receptor through radioligand binding assays and determine the functional activity and selectivity of the ligands using adenylyl cyclase assay, and (4) Evaluate promising ligands to determine their ability to cross the blood brain barrier and achieve CNS penetration for selecting compounds for further studies. The proposed effort involving a team of researchers with experience in drug design, synthetic medicinal chemistry, computational chemistry and biochemistry and pharmacology should, in addition to enhancing our basic understanding of ligand-receptor interactions, lead to the discovery and development of new pharmacological tools and medications for the treatment of drug addiction and for prevention of relapse to drug use. PUBLIC HEALTH RELEVANCE: Addiction to stimulant drugs such as cocaine and methamphetamine has a huge impact on the health and well-being of a large number of individuals and imposes a significant burden on the health care system. Results from recent research indicate that compounds that selectively interact with the D3 subtype of dopamine receptor could potentially be useful for treatment of addiction and for prevention of relapse to drug taking. The discovery and development of medications for the treatment of addiction to cocaine, methamphetamine, and related psychostimulants through the proposed research effort will therefore have a significant beneficial impact on the society and public health.