Exploration of Structure-Activity Relationships for Dual Serotonin Transporter Reuptake Inhibitors-Histamine H3 Receptor Antagonists

Depression is a major health issue, which is routinely treated with selective serotonin reuptake inhibitors. However, although these agents display a favorable effect on mood, they often fail to improve conditions that accompany depression including cognitive impairment and fatigue. In pre-clinical studies histamine H3 receptor antagonists have demonstrated both pro-cognitive and wake-promoting effects suggesting that the combination of a histamine H3 receptor antagonist and a serotonin reuptake inhibitor may have utility as an antidepressant therapy. To this end we sought to introduce histamine H3 receptor antagonist activity into both known selective serotonin reuptake inhibitors and novel templates. These efforts have afforded several series of compounds with the desired activities. Selected examples demonstrated in vivo efficacy both in pre-clinical models of depression and wakefulness.