New treatments for stress-related disorders including depression, anxiety and Substance Use Disorder are greatly needed. Kappa opioid receptors (KORs) are expressed in central nervous system, including areas implicated in analgesia and affective state. Although KOR agonists share the antinociceptive effects of mu opioid receptor (MOR) agonists, they also tend to produce negative affective states. In contrast, selective KOR antagonists have antidepressant- and anxiolytic-like effects, stimulating interest in their therapeutic potential. The prototypical KOR antagonists (e.g., norBNI, JDTic) have an exceptionally long duration of action that complicates their use in humans, particular in tests to establish safety. This study was designed to test dose- and time-course effects of novel KOR antagonists with the goal of identifying short-acting lead compounds for future medication development.