An Innovative Auto-Antagonistic Multi-Target Strategy: MOR/DOR/NPFFR2 Agonists Achieve Separation of Analgesia from Side Effects
Pengtao Li, Yaofeng Zhao, Tong Yang, Lechun Ma, Zhanyu Niu, Zhonghua Zhang, Huiming Bao, Zhengkun Liu, Mingmin Huang, Hongyang Man, Shouliang DongAbstract
Long-term opioid analgesia is limited by severe adverse effects. We propose an auto-antagonistic multitarget strategy incorporating NPFFR2-mediated counter-regulation to limit excessive opioid effects while preserving analgesia. Structure-guided optimization of MCRT yielded analogs 1, 4, and 9, which function as MOR/DOR/NPFFR2 triple agonists. Analog 1 provided pharmacological proof-of-concept, exhibiting characteristic bell-shaped antinociceptive and gastrointestinal dose−response profiles sensitive to RF-9 blockade. Together with its NPFFR2 agonism and no detectable NPFFR1 agonism in vitro, these findings support a contribution of NPFFR2-mediated counter-regulation to its self-limiting profile. In contrast, analogs 4 and 9 displayed dose-dependent analgesia and distinct in vivo profiles. All three analogs produced robust antinociception in CFA-induced inflammatory pain and showed no detectable tolerance or persistent gastrointestinal inhibition during repeated treatment, while analogs 1 and 4 showed no detectable withdrawal, conditioned place preference, or motor impairment. These findings support the auto-antagonistic strategy as a framework for developing safer analgesics.