The goal of the research described in this application is to develop therapeutic agents that can be used to treat cocaine addiction. The strategy taken will be to synthesize and pharmacologically evaluate antagonists that are selective for the dopamine D3 receptor. The D3 receptor was chosen as the molecular target for drug development because of recent reports demonstrating that the behavioral and reinforcing effects of cocaine, an indirect dopamine agonist, are mediated through the activation of this receptor. Antagonists of the D2 class of receptors have not demonstrated great success in treating cocaine addiction because of their tendency to cause adverse motoric side effects. The failure of this approach can be attributed to the use of dopamine receptor antagonists such as haloperidol that have a higher affinity for D2 versus D3 receptors. A D3 receptor antagonist having a low affinity for D2 receptors is likely to succeed since this binding profile will result in a high blockade of mesolimbic D3 receptors (attenuating cocaine reinforcement) and a low occupancy of D2 receptors (resulting in a low tendency to cause extra pyramidal side effects). However, there is currently a shortage of D3-selective antagonists having a suitable D3 versus D2 receptor affinity to test this hypothesis. An additional incentive for focusing on D3 receptors as our target for drug development stems from our recent identification of a series of D3-selective compounds, which are suitable lead compounds for further structure-activity relationship studies. Functional assays have determined that these compounds are antagonists of the D-class of receptors. The goal of this project is to improve both the D3 binding affinity and the selectivity of our lead compounds for D3 versus D2 receptors. Once a suitable compound is identified, the corresponding iodine-125 labeled analogue will be prepared and in vitro binding studies (Scatchard analyses, kinetic studies) of the D3 receptor will be conducted. The results of this research will produce D3-selective antagonists that have the potential for treating cocaine abuse. In addition, this research will result in the development of radiolabeled probes for studying both the function of D3 receptors in the CNS and the alteration in D3 receptor density thatoccurs as a consequence of cocaine abuse.
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