Synthesis of 8-thiabicyclo[3.2.1]oct-2-enes and their binding affinity for the dopamine and serotonin transporters

The reinforcing and stimulant properties of cocaine have been primarily associated with its propensity to bind to monoamine transport systems, in particular the dopamine transporter. Inhibition of the dopamine transporter then leads to an increase of synaptic dopamine with substantial pharmacological consequences. The search for medications for cocaine abuse has had a particular focus on tropane analogs of cocaine, and the interchange of nitrogen for oxygen in this class has led to potent and selective inhibitors of monoamine transport. Herein we report that 8-thiatrop-2-enes are highly potent and quite selective inhibitors of the dopamine transporter. The 3,4-dichlorophenyl-8-thiabicyclo[3.2.1]oct-2-ene (4f) is particularly potent (IC50 = 4.5 nM) and selective (800-fold) with respect to inhibition of the serotonin transporter.