The endogenous monoamines, dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters, their biological receptors, and their reuptake mechanisms are the focus of considerable research since modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes.1–8 Dopamine, serotonin and norepinephrine are released into the synapse where their concentrations are regulated, at least in part, by reuptake proteins located in the presynaptic membrane.9,10 These reuptake mechanisms have been termed the dopamine transporter (DAT), serotonin transporter (SERT), and the norepinephrine transporter (NET). The DAT is the target of numerous therapeutic agents such as Ritalin® (methylphenidate), Adderral® (amphetamine), Wellbutrin® or Zyban® (bupropion). Our interest has focused on the DAT in a search for medications for cocaine abuse2,11–14 since cocaine’s reinforcing and stimulant properties have long been associated with its propensity to bind to and inhibit monoamine transport systems, especially the DAT.15–24 Our work has concentrated on the design of compounds that inhibit all three monoamine uptake systems with different degrees of potency and selectivity. In the search for a new class of compounds that may provide a different access to agents that target the transport systems, our attention was drawn to bupropion (Figure 1), a compound marketed as an antidepressant (Wellbutrin®) as well as for smoking cessation (Zyban®). Bupropion is a 2-substituted aminopropiophenone,25,26 that has been explored extensively. Interestingly, and of relevance to the work which we describe later, the enantiomers of bupropion may not differ in their ability to inhibit biogenic amines.27 Bupropion is structurally closely related to a 2-substituted aminopentanophenone, pyrovalerone (Figure1).