SYNTHESIS, BIOLOGICAL ASSESSMENT OF CANDIDATE MEDICATIONS FOR STIMULANT ABUSE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: The stimulant and reinforcing properties of cocaine, correlate with its ability to inhibit monoamine transporters, e.g. dopamine (DAT), and serotonin (SERT) transporters, in brain (e.g. striatum, nucleus accumbens). Cocaine blockade of monoamine transporters results in elevated extracellular concentrations of dopamine, resulting in enhanced stimulation medicated by dopamine receptor activity. The search for pharmacotherapies for cocaine addiction has focused on the design of compounds that bind selectively to the DAT but with slow onset of DAT occupancy and extended duration of action. Phenyltropane analogs of cocaine, of which CFT (WIN 35,428) is the prototype, have offered promising leads for the discovery of DAT selective inhibitors. Building on our previous studies indicating that an amine nitrogen in the 8-aza position is not a prerequisite for potent inhibition of monoamine inhibition, we discovered that 8-thiatropanes retain substantial DAT binding potency and DAT:SERT selectivity. Presently, we evaluate replacing the 2-carbomethoxy group with a 2-isoxazole. METHODS: Binding experiments initially were established using tissue homogenates from primate brain and then applied to cloned human transporters expressed in HEK-293 cells. RESULTS: This new class of 8-thiabicyclo(3.2.1)octanes displayed potent and selective DAT inhibition, with the 3b-aryl compounds particularly potent (IC50 = 743 nM). In both the 3a-aryl and 3b-aryl series, the 3-methylisoxazole manifested superior DAT inhibitory potency and selectivity compared with the 3-phenylisoxazoles. CONCLUSIONS: The results with this new class of 8-thiatropanes suggests further evaluation is warranted.