Design, synthesis, and structure–activity relationship of novel opioid κ-agonists

We designed and synthesized a novel opioid κ-agonist, TRK-820, which showed potent analgesic activity without addiction and aversion. By focusing on 4,5-epoxymorphinan, a traditional opioid skeleton but a new structure in the opioid κ-agonist research field, and by rationally applying the ‘message-address concept’ and ‘accessory site hypothesis,’ we discovered a new chemical class opioid κ-agonist, TRK-820 ( 1). Its development as an antipruritus is now in the final stage. Here, the full scope of its design, synthesis, and structure–activity relationship are described.