Dopamine transporter as target for drug development of cocaine dependence medications

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Abstract

Because much evidence implicates the dopamine transporter in the reinforcing effects of cocaine, development of potential medications for cocaine dependence has included the dopamine transporter as a target. The present overview covers progress in the drug development area regarding several classes of dopamine uptake inhibitors, with an emphasis on structure–activity relationships that enhance potency and selectivity at transporters for dopamine compared with those for serotonin or norepinephrine. The following categories of compounds are covered: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR), methylphenidate, mazindol, and phencyclidine analogs. Activity at transporters as well as on behavior is highlighted.

Introduction

Cocaine is a naturally occurring molecule that is well known for its strong reinforcing activity and abuse potential (Johanson and Schuster, 1995). Addiction to cocaine is a major problem in our society today causing financial problems and posing a burden in securing law and order. Moreover, it has also contributed to the spreading of Human Immunodeficiency Virus (HIV) infection as needle sharing is a pervasive problem among drug abusers. At present, no effective medication is available for the treatment of cocaine addiction and there is an urgent need for the development of an effective medication. Cocaine binds to all three monoamine neurotransporter systems in the brain (Ritz et al., 1990). It has been established that binding of cocaine to the dopamine transporter, resulting in decreased clearance of neuronally released dopamine, is responsible for its strong reinforcing effects Ritz et al., 1987, Spealman et al., 1989. The dopamine hypothesis of cocaine addiction received further support from a series of in vivo experiments Kuhar et al., 1991, Koob and Bloom, 1988, Witkin et al., 1991 and also from molecular biological studies involving dopamine transporter knockout mice (Giros et al., 1996). Thus, binding potencies of dopamine receptor agonists and dopamine transporter specific compounds correlated very well with their relative reinforcing effects in animal drug discrimination and self-administration experiments Spealman et al., 1989, Witkin et al., 1991. Furthermore, in a microdialysis study, it was demonstrated that cocaine increases dopamine preferentially in the nucleus accumbens in relation to its reinforcing effects (Di Chiara and Imperato, 1988). More recently, the dopamine hypothesis for cocaine's reinforcing effects was further strengthened by the demonstration that in dopamine transporter knockout mice cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens but not in the caudate putamen (Carboni et al., 2001). This observation perhaps explains the results of a recent experiment showing self-administration of cocaine by dopamine transporter knockout mice (Rocha et al., 1998) as in these mice cocaine will still block the norepinephrine transporter, which is known to accumulate dopamine efficiently (Yamamoto and Novotney, 1998), in the nucleus accumbens and, thus, will increase the extracellular concentration of dopamine (Eshleman et al., 1999). Finally, in recent Positron Emission Tomography (PET) studies, it was very elegantly demonstrated that the subjective effect of cocaine in humans directly correlates with the extent to which it occupies the dopamine transporter (Volkow et al., 1997). These results support a drug development approach targeting the dopaminergic system as a viable avenue to develop medications for cocaine addiction (Smith et al., 1999).

As the relationship between cocaine binding to the dopamine transporter and reinforcing activity was strongly established, this transporter became a logical choice for drug development. A number of approaches have been taken to develop medications for cocaine addiction McCance, 1997, Carroll et al., 1999, Mello and Negus, 1996, Platt et al., 2002. The two primary strategies are based on either the concept of substituting a non-addictive treatment agent, e.g. agonist, for cocaine, or the idea of antagonizing the reinforcing effect of cocaine. These ideas are primarily rooted in the successful application of these strategies in the treatment of opioid addiction. Substitution therapies with full and partial agonists have been applied with success in the treatment of heroine and nicotine addiction. An ideal profile of a pharmacotherapeutic agent in substitution therapy consists of decreasing self-administration of cocaine over a wide range of doses by depressing its overall rewarding quality. However, the drug by itself should have little or no abuse liability and it should produce some of the subjective effects of cocaine thus reducing its craving (Howell and Wilcox, 2001, Gorelick, 1998, Carroll et al., 1999). A potential medication for substitution therapy should have the following properties: (1) The agent should enter the brain slowly. (2) It should exhibit an appropriately long duration of action to provide a suitable dosing schedule. (3) The drug should be target specific and should exhibit minimum side effects (Glowa, 1996). Site-directed mutagenesis results suggested that cocaine and dopamine do not share identical binding sites raising the expectation for developing a cocaine antagonist (Kitayama et al., 1992). Such antagonists, if developed, will find an application in reducing cocaine self-administration, by reducing its reinforcing activity. It may also find a useful application in reducing toxicity from cocaine overdose.

Section snippets

Different structural classes of molecules targeting the dopamine transporter

A great number of structurally diverse compounds have been developed for the dopamine transporter with the aim to develop effective pharmacotherapies for cocaine addiction Singh, 2000, Carrol et al., 2002. These compounds can be classified in the following categories: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909)-analogues, methylphenidate, mazindol and phencyclidine analogs. The representative structure for each class of molecules is

Concluding remarks

It is clear from the above overview that intense drug development efforts have targeted the dopamine transporter in order to find leads for medications useful in the treatment of cocaine dependence. Progress has been made in the area of potential leads for a substitution therapy, with compounds identified that have a slow onset and long duration of action, such as RTI-113 (Fig. 6), PTT (Fig. 6), and GBR 12909 (Fig. 8) in decanoate form. Structural refinements will be needed to enhance

Acknowledgements

Much of the work covered in Section 2.3 was supported by NIH/NIDA grants (DA 08647 and DA 12449 to A.K.D).

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