The primary goal of this project is to develop compounds that have potential utility as therapeutic agents for cocaine addiction. The primary objectives are to synthesize and evaluate the pre-clinical biological and behavioral effects of novel compounds targeted for the dopamine transporter. These compounds are designed to elucidate the mechanism of action of the dopamine transporter (DAT). As such, a better understanding of the mechanisms of action of dopamine uptake inhibition may provide leads toward the development of a cocaine therapeutic agent.
The specific aims of the proposed research are focused on the study of the SAR of novel analogues of tropane/GBR 12909 hybrids. Lead compounds identified in the previous granting period (alkylidenyttropane/GBR 12909 hybrid analogues and 2-(diarylmethoxymethyt)-3a-aryltropanes) will be studied further in vitro and in vivo. These compounds will also serve as templates for new SAR studies aimed at the development of more potent and selective DAT ligands. In addition, the search for less lipophilic GBR 12909 analogues will continue with the aim to provide novel pharmacological probes to explore the relationship between the onset of activity and abuse liability. A secondary objective is to synthesize novel meperidine analogues to be employed in a limited SAR study to identify potential compounds that may be useful to explore the heterogeneous character of the dopamine transporter (a high affinity site and a low affinity site). Studies have suggested that the high affinity sites plays a role in the abuse liability of cocaine; however, these studies are far from conclusive and are hampered by the lack of pharmacological tools to selectively affect either of these sites. The 3',4""""""""-dichloromeperidine (SAL-V-11) identified in the previous granting period will serve as a template for studies aimed at the identification of a site-selective DAT ligand.
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