Dual-target mu opioid-dopamine D₃ receptor (MOR-D₃R) ligands based on etonitazene: New leads for transforming “nitazenes” into novel analgesics

The development of opioid analgesics with low abuse liability remains a challenge. As dopamine D₃ receptor (D₃R) antagonists/partial agonists can reduce opioid self-administration and reinstatement in animals while augmenting antinociceptive effects, a dual-target ligand strategy was investigated. Here, the high affinity mu opioid receptor (MOR) agonist etonitazene was modified by incorporating various D₃R pharmacophores with varying linking chains. N-substituted etonitazene analogs 31 (MOR K_i = 33.4 nM; D₃R K_i = 90.6 nM), 35 (MOR K_i = 29.7 nM; D₃R K_i = 53.8 nM), and 43 (MOR K_i = 89.6 nM; D₃R K_i = 45.4 nM) achieved balanced binding affinities and were chosen as lead molecules. In vitro bioluminescent resonance energy transfer (BRET) assays confirmed that all three compounds functioned as MOR agonists and D₃R antagonists/partial agonists. Notably, compound 31 demonstrated metabolic stability and maximal antinociceptive effects (ED₅₀ = 29.1 mg/kg s.c.) with reduced motor stimulation in C57BL/6J mice. Although compound 31 produced respiratory depression at the analgesic dose of 30 mg/kg, this was comparable to morphine which has lower intrinsic efficacy and a safer profile compared to etonitazene. Overall, our findings support the feasibility of developing MOR-D₃R dual-target ligands, based on etonitazene, as efficacious analgesics that may have reduced addictive liability.