SLL-023ACP, a KOR/MOR dual agonist, produces potent antinociception with fewer side effects

Opioids have served as the first-line treatment for pain management. However, their side effects such as addiction potential and constipation have limited their clinical use. Here, we characterized a novel 4,5-epoxymorphinan-based derivative SLL-023ACP, which we previously identified as a high affinity ligand towards κ-opioid receptor (KOR) and μ-opioid receptor (MOR). SLL-023ACP was identified as a full KOR agonist (EC₅₀ = 12.84 nM, E_max = 85.69%) and MOR partial agonist (EC₅₀ = 31.21 nM, E_max = 54.49%) in vitro functional cAMP inhibition assay. In vivo, SLL-023ACP displayed potent antinociceptive effects with ED₅₀ values of 2.6 mg/kg in the hot plate test and 0.15 mg/kg in the abdominal constriction test, exhibiting greater potency than KOR agonist U50,488H and MOR agonist Morphine. Its antinociceptive action is effectively reversed by the non-selective opioid antagonist naloxone and the MOR antagonist CTAP in the hot plate test, and by the KOR antagonist nor-BNI in the abdominal constriction test, indicating its analgesic effects was via MOR and KOR. Importantly, at analgesic doses (2.6 and 5 mg/kg), SLL-023ACP induced no conditioned place preference (CPP) and caused less constipation than morphine, although it did produce significant sedation. Taken together, these results suggest that SLL-023ACP is a potent dual KOR/MOR agonist with a favorable profile of potent analgesia with reduced addiction liability and gastrointestinal dysfunction.