Preclinical Targets for Stimulant Addiction

Since there are no FDA-approved medications for the treatment of cocaine and amphetamine addiction, intensive efforts have been directed toward discovering medication candidates. In this regard, over the past decade, a focus on elucidating mechanisms underlying the reinforcing effects and addictive liability of cocaine, as well as those underlying relapse, has prompted the identification of receptor/transporter candidates for drug discovery. Although many targets have been proposed, the following receptors/transporters and examples of promising drug candidates that have high affinity and selectivity for these targets have been widely studied and currently hold the most potential for medication development.

The monoamine neurotransmitter transporters are the principle sites of action of the psychostimulants cocaine and methamphetamine. These psychostimulants bind to the monoamine transporters and inhibit the reuptake of their respective neurotransmitters. Methamphetamine is further transported into the neuron and binds to the vesicular monoamine transporter (VMAT), resulting in a release of neurotransmitter into the synapse by disruption of vesicular storage and reverse transport. The psychostimulant actions of these drugs are primarily due to the release of DA, which stimulates postsynaptic DA receptors. However, especially with methamphetamine, there is also significant release of serotonin. A widespread concern with methamphetamine is its increasing use and its neurotoxic potential. Thus, identifying medications that prevent these illicit drugs from producing their actions is of primary importance in drug abuse research. Thus, a large investment in discovering and developing novel DA uptake inhibitors, both selective for DAT and also nonselective monoamine transport inhibitors has transpired over the past 15 years, resulting in an arsenal of compounds, based on cocaine, GBR 12909, benztropine, mazindol, methylphenidate, and rimcazole.53'77'78 Many of these compounds demonstrate a cocaine-like behavioral profile in animal models, and could be potential 'substitute' therapy candidates. Several compounds have been identified that are potent and selective DA uptake inhibitors but do not produce cocaine-like behavioral effects. Importantly, some of these compounds attenuate cocaine-induced behaviors, such as cocaine-induced locomotor activity and the cocaine discriminative stimulus in animals.79 Examples of DAT inhibitors that show promise in this regard and are in various stages of preclinical development can shown in Figure 9. The novel DAT inhibitor RTI 336 represents the enormous class of 3-phenyltropane analogs reported over the years as high-affinity DAT inhibitors.77 In general these drug candidates have longer durations of action than cocaine, but are cocaine-like in most animal models of cocaine abuse. Although GBR 12909 (Figure 8)

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