Chronic pain and depression are both widely prevalent comorbid medical conditions. While efficient, μ-opioid receptor-based medications are associated with life-threatening side effects, including respiratory depression, dependence, and addiction. The δ-opioid receptor is a promising alternative biological target for chronic pain and depression due to its significantly reduced on-target side effects compared to the μ-opioid receptor. A previous study identified two δ-opioid receptor positive allosteric modulators. Herein, we report the design of five series of compounds targeting previously unexplored regions of the originally described SAR. Analogs were assessed for their ability to potentiate the agonist response of Leu-enkephalin. Of the 30 analogs, compound displayed trends toward enhancing the ERK1/2 phosphorylation signaling compared to cAMP inhibition, while compound exhibited a trend in shifting the signaling bias toward cAMP inhibition. Both and emerged as promising tool compounds toward the design of prospective therapeutics requiring specific downstream signaling attributes.