The elucidation of the neurochemical mechanisms underlying the reinforcing effects of cocaine has lead to targeted research on strategies for the development of pharmacological treatments for cocaine abuse and addiction. Cocaine inhibits the reuptake of the monoamine neurotransmitters dopamine, serotonin and norepinephrine into their respective neurons resulting in an increase in basal levels of these substances in their respective synapses. To date, it is the overstimulation of dopamine receptors by the endogenous neurotransmitter that has been identified as the most likely neurochemical mechanism underlying cocaine's reinforcing effects. Since there are five receptor subtypes in two families of dopamine receptors namely D1 (D1 and D5) and D2 (D2, D3, D4), it is of interest to characterize the role, if any, each dopamine receptor subtype may play in the pharmacological effects of cocaine. In order to achieve these goals, highly selective and potent ligands for each receptor subtype must be developed. Recently, behavioral and neuroanatomical evidence in animal models of cocaine abuse has suggested that dopamine D3 receptors may influence the behavioral effects of cocaine. For example, it has been demonstrated that a purported D3 receptor antagonists may be able to block some of the pharmacological effects of cocaine. In addition, a selective D3 partial agonist has been reported to attenuate 'drug-craving' in rats trained to self-administer cocaine. As a result of these investigations we have embarked on a new study to design and prepare novel D3 dopamine receptor ligands. Based on structure-activity relationships (SAR) reported in the literature and results of screening 26 compounds from our laboratory that had structural components that were similar to those reported to be important for dopamine D3 receptor binding, we developed a design strategy for novel D3 ligands. We have synthesized 15 novel compounds that incorporated the following structural features: 1) terminal tricyclic aromatic moiety, 2)amide with 3-5 carbon chain linker, 3) aryl-substituted piperazine. All compounds were evaluated for binding in a human D3 receptor transfected CHO cell line. In addition, all compounds were evaluated for binding in D2 and D4 transfected cell lines and for binding at noradrenergic alpha 1 receptors. The results of these initial studies demonstrated the following SAR for D3 receptors in this series of compounds. A tricyclic aryl terminus is well tolerated at D3 receptors. An amide function appears to be required and at least a 4-carbon linker gives higher affinity binding at D3 than the shorter chain links. The 2,3-dichloro-aryl substituted piperazine ring provided optimal binding affinity at D3. The most potent and selective D3 ligand in this initial series demonstrated a Ki=1.6 nM at D3 with a D3/D4 selectivity ratio of 200 and a D3/D2 selectivity ratio of 100. The most selective and potent D3 ligand in this series is being evaluated in several rodent models of cocaine and amphetamine abuse. These studies will provide information on the role D3 receptors play in the psychostimulant actions of these drugs of abuse. Further optimization of this series of compounds is underway with a particular focus on the carbon linking chain between the aryl termini. These studies are anticipated to provide a highly selective dopamine D3 receptor subtype ligand that can be used for behavioral evaluation in animal models of cocaine abuse. Furthermore, the SAR deduced from these and other studies will provide useful structural information that can be applied to the development of molecular tools such as irreversible and/or radiolabeled ligands. These ligands will enable further characterization of the structure and function of the D3 dopamine receptor subtype and its role in psychostimulant abuse.
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