Cocaine is responsible for more serious intoxications and deaths than any other illicit drug, yet no effective treatments for cocaine abuse are currently available. One strategy for developing effective anti-cocaine agents is to block cocaine's access to its target proteins. Of the myriad of sites through which cocaine can act, sigma receptors are among the most promising targets for drug development. In earlier studies, our group synthesized and identified over two dozen sigma receptor antagonists that prevented cocaine-induced convulsions, lethality, and locomotor activity. The effective compounds are all analogs of the synthetic ligand BD1008, and four series of modifications to the chemical structure of this compound were evaluated in our previous investigations: 1) N-alkyl substitutions, 2) pyrrolidinyl ring modifications, 3) aryl monosubstitutions, and 4) conformational restrictions. As a result, we have identified specific modifications from each synthetic series that are most effective against cocaine-induced behaviors. However, compounds that incorporate combinations of the best structural features have yet to be made and tested. We hypothesize that by combining the best structural features of our existing compounds, optimal compounds with enhanced anticocaine actions can be achieved. Thus, the specific aims of the project are: 1) to develop novel ligands with pharmacophoric potential by combining optimal structural features from our earlier sigma1 antagonists possessing anti-cocaine actions, 2) to confirm that similar to their predecessors, the novel compounds possess high affinity for sigma1 receptors but lack interactions with non-sigma sites, 3) to confirm that the novel compounds attenuate cocaine-induced behaviors, but do not produce unfavorable side effects that could compromise their clinical potential, and 4) to evaluate structure-activity relationships. It is anticipated that the results of this project will lead to the development of new and effective treatments for cocaine addiction and overdose.
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