Chapter 17: The Rational Design of Triple Reuptake Inhibitors for the Treatment of Depression

Despite advances in treatment, major depression continues to be a disabling condition that exacts an enormous toll on society, both socially and economically. A significant advance in the treatment of depression was associated with the discovery of the selective serotonin reuptake inhibitors (SSRIs), agents that increase brain levels of serotonin, and the serotonin and norepinephrine reuptake inhibitors (SNRIs), which exert their action on both the serotonergic and noradrenergic pathways. Unfortunately, only one-third of patients respond positively to SSRI/SNRI treatment, and they are associated with a considerable delay in the onset of action. In order to improve on both remission rates and time to onset, many psychiatrists add an additional drug to a patient's SSRI or SNRI regimen. A widely used drug for this augmentation strategy is bupropion, a norepinephrine and dopamine reuptake inhibitor (NDRI). This combination results in the increase of synaptic concentrations of serotonin, norepinephrine, and dopamine, effectively creating a triple reuptake inhibitor (TRI). This chapter will focus on our strategies to discover novel triple reuptake inhibitors through scaffold hopping. In addition to potency optimization, strategies utilized to address other inherent issues such as blood–brain barrier penetration, microsomal clearance, hERG interactions, and drug–drug interactions will also be discussed.