The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D<sub>3</sub> receptor (D<sub>3</sub>R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the D<sub>3</sub>R as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and D<sub>3</sub>R. Structure-activity relationship studies using computationally aided drug design and <i>in vitro</i> binding assays led to the identification of potent dual-target leads (<b>23</b>, <b>28</b>, and <b>40</b>), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-D<sub>3</sub>R antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.