For the treatment of pain, the design of a bifunctional mu-opioid receptor (MOR)/delta-opioid receptor (DOR) agonist is an effective strategy to seek safer opioids with higher antinociceptive efficacy and diminished adverse side effects. Herein, we describe the design, synthesis, and evaluation of a novel bivalent ligand (SW-WL-2) with a methyl 1-(3-methoxy-3-oxopropyl)-4-(phenylamino) piperidine- 4-carboxylate moiety (remifentanil derivative) covalently linked to a dermorphin-like structure (H-Dmt-N-Me-D-Ala-Aba-Gly-NH₂, BVD03) at the C-terminus. Our results showed that SW-WL-2 behaved as a potent dual agonist of MOR and DOR with significant and prolonged antinociceptive effects in acute pain models in vivo. Furthermore, SW-WL-2 exhibited reduced or no opioid-like side effects such as physical dependence or respiratory depression, in contrast to an equipotent analgesic dose of morphine or BVD03. Thus, SW-WL-2 should be used as a new lead compound for the discovery of safer opioid drugs for the treatment of pain.

对于疼痛的治疗，双功能μ-阿片受体（MOR）/δ-阿片受体（DOR）激动剂的设计是寻求更安全的阿片类药物的有效策略，具有更高的镇痛功效和更少的不良副作用。在此，我们描述了一种新型二价配体 ( SW-WL-2 )的设计、合成和评估，其具有甲基 1-(3-甲氧基-3-氧代丙基)-4-(苯氨基)哌啶-4-羧酸酯部分 (瑞芬太尼衍生物）在 C 端与皮啡肽样结构（H-Dmt- N -Me -D-Ala-Aba-Gly-NH ₂ ，BVD03）共价连接。我们的结果表明，SW-WL-2是一种有效的 MOR 和 DOR 双重激动剂，在体内急性疼痛模型中具有显着和持久的镇痛作用. 此外，与等效镇痛剂量的吗啡或 BVD03 相比，SW-WL-2表现出减少或没有类阿片样副作用，例如身体依赖或呼吸抑制。因此，SW-WL-2应作为新的先导化合物用于发现更安全的阿片类药物来治疗疼痛。