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Benzylpiperidine derivatives as new dual μ-opioid and σ 1 receptor ligands with potent antinociceptive effects

Bioorganic Chemistry, ISSN: 0045-2068, Vol: 153, Page: 107921
2024
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Article Description

Dual-acting μ-opioid receptor (MOR)/sigma-1 receptor (σ 1 R) ligands have displayed promise in exerting robust antinociceptive effects while reducing opioid-related side effects. To discover safer and more effective analgesics, we designed, prepared, and evaluated 30 benzylpiperidine derivatives as dual MOR and σ 1 R ligands. The obtained benzylpiperidine analogs were tested for MOR and σ 1 R binding affinity in vitro. The best compound 52 showed high affinity for both MOR [ K i (MOR) = 56.4 nM] and σ 1 R [ Ki (σ 1 R) = 11.0 nM] and produced potent antinociceptive effects in the abdominal contraction test (ED 50  = 4.04 mg/kg in mice), carrageenan-induced inflammatory pain model (ED 50  = 6.88 mg/kg in mice), formalin test (ED 50  = 13.98 mg/kg in rats) and complete Freund’s adjuvant (CFA)-induced chronic pain model (ED 50  = 7.62 mg/kg in mice). Moreover, 52 had less MOR-related adverse effects than oxycodone, including constipation, acute hyperlocomotion and physical dependence. The above results suggested that 52 may be a promising candidate for the development of safer analgesics.

Bibliographic Details

Li, Zong-Zheng; Wang, Zhen; Chen, Xiong; Feng, Hong-Qing; Yao, Xing-Yu; Song, Jie; Xu, Ben; Jin, Jian; Cao, Xudong; Zhuang, Tao

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics; Chemistry

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