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Papers of the Week

Papers: 20 Aug 2022 - 26 Aug 2022

Animal Studies, Pharmacology/Drug Development

2022 Aug 05

Eur J Med Chem


Benzylaminofentanyl derivates: Discovery of bifunctional μ opioid and σ receptor ligands as novel analgesics with reduced adverse effects.


Zhuang T, Xiong J, Ren X, Liang L, Qi Z, Zhang S, DU W, Chen Y, Liu X, Zhang G
Eur J Med Chem. 2022 Aug 05; 241:114649.
PMID: 35961067.


To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ receptor (σR) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K = 6.5 nΜ; EC = 48.5 nΜ, E = 66.3%) and σR antagonism (K = 35.7 nM) in vitro, and exerted powerful analgesic effects in the abdominal constriction test (ED = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED = 0.30 mg/kg, in mice). The contributions of MOR and σR to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σR agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects-including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion-than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σR ligands as a promising avenue for the development of potent and safe analgesics.